Pharmaceutical compositions of fumaric acid esters

ABSTRACT

Pharmaceutical compositions and dosage forms of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and/or methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate, containing low levels of certain impurities are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplication No. 61/969,488, which was filed Mar. 24, 2014 and isentitled Pharmaceutical Compositions of Fumaric Acid Esters. Thecontents of the above mentioned application is hereby incorporated byreference in its entirety.

TECHNICAL FIELD

Disclosed herein are pharmaceutical compositions of fumaric aciddi-esters having low levels of undesirable impurities.

BACKGROUND

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is adi-ester of fumaric acid and a prodrug of monomethyl fumarate, and isalso referred to as (N,N-Diethylcarbamoyl)methyl methyl fumarate. Thecompound has a molecular weight of 243 daltons and the followingchemical structure:

The compound can synthesized by reacting monomethyl fumarate with2-chloro-N,N-diethylacetamide in the presence of CsHCO₃. Other methodsof synthesizing the compound are described in Gangakhedkar et al. U.S.Pat. No. 8,148,414.

Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is also a di-esterof fumaric acid and a prodrug of monomethyl fumarate. The compound isalso sometimes referred to as Methyl (4-morpholinobutyl) fumarate. Thecompound has a molecular weight of 271 daltons and the followingchemical structure:

The compound can synthesized by activating monomethyl fumarate with1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride indichloromethane, followed by addition of 4-Morpholin-4ylbutyl-1-ol and4-N,N-dimethylaminopyridine. Other methods of synthesizing the compoundare described in Cundy et al. U.S. Patent Publication No. 2013/0203753,filed Feb. 7, 2013.

Fumaric acid esters have been proposed for use in treating awide-variety of diseases and conditions involving immunological,autoimmune, and/or inflammatory processes including psoriasis (Joshi andStrebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah,Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, ClinicsDermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonarydiseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiacinsufficiency including left ventricular insufficiency, myocardialinfarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi etal., US 2007/0027076); mitochondrial and neurodegenerative diseases suchas Parkinson's disease, Alzheimer's disease, Huntington's disease,retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi andStrebel, WO 2002/055063, US 2006/0205659, U.S. Pat. Nos. 6,509,376,6,858,750, and 7,157,423); transplantation (Joshi and Strebel, WO2002/055063, US 2006/0205659, U.S. Pat. Nos. 6,359,003, 6,509,376, and7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404);autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. Nos.6,509,376, 7,157,423, and US 2006/0205659) including multiple sclerosis(MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Wentand Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006,13, 604-610; and Schilling et al., Clin Experimental Immunology 2006,145, 101-107); ischemia and reperfusion injury (Joshi et al., US2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899);inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis; arthritis; and others (Nilsson et al., WO 2006/037342 andNilsson and Muller, WO 2007/042034).

Many pharmaceutically active agents are susceptible to photodegradationupon exposure to sunlight and/or UV light. Generally, incorporation oflight absorbers into formulations can stabilize these photosensitiveagents to some extent. For example, N. Jamil et al. (“Studies of thephotostability of reserpine in parenteral solutions”, Die Pharmazie, 38:467-469 (1983)), refers to studies done on the photostability ofreserpine in parenteral formulations and the effects of some commonlyused stabilizers. U.S. Pat. No. 6,379,697, titled “Stabilization ofphotosensitive materials” to Gregoriadis, et al. refers to liposomescontaining a photosensitive material together with a light absorbingmaterial capable of increasing the photostability of the photosensitivematerial.

Griffin et al. (“The chemistry of photodimers of maleic and fumaric acidderivatives. I. Dimethyl fumarate dimer”, J Am Chem Soc (1961), 83:2725-2728), disclose that dimethyl fumarate degrades in the presence oflight to form the photodimer compound tetramethylcyclobutane-1,2,3,4-tetracarboxylate. See also Griffin et al. U.S. Pat.No. 3,139,395.

SUMMARY

Thus, in a first aspect, a pharmaceutical dosage form for treating adisease in a patient is provided, comprising:

-   (a) a therapeutically effective amount of    (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; and-   (b) one or more compounds of Formulae (I), (II), (III), (IV), (V),    (VI), (XIII), or (XV):

N,N-diethyl-2-hydroxyacetamide,

-   and salts of any of the foregoing, wherein:-   each of R¹ through R⁴ is independently chosen from hydrogen, methyl    and (N,N-diethyl carbamoyl)methyl;-   each R⁵ and R⁷ is independently chosen from hydrogen, methyl, and    (N,N-diethyl carbamoyl)methyl;-   Y is chosen from O, S, NH and NR⁸;-   R⁶ is chosen from hydrogen, lower alkyl, substituted lower alkyl,    aryl, and substituted aryl;-   R⁸ is chosen from lower alkyl;-   each of R⁹ and R¹⁹ is independently chosen from hydrogen, methyl,    and (N,N-diethyl carbamoyl)methyl;-   each of R¹¹ and R¹² is independently chosen from hydrogen, methyl,    and (N,N-diethyl carbamoyl)methyl;-   each of R¹³ and R¹⁴ is independently chosen from hydrogen, methyl,    and (N,N-diethyl carbamoyl)methyl;-   Q is —O—, —S—, —NH—, —N(R¹⁷)—, or —C(R¹⁸)₂—;-   each of R¹⁵ and R¹⁶ is independently chosen from hydrogen, methyl,    and (N,N-diethyl carbamoyl)methyl;

R¹⁷ is (N,N-diethylcarbamoyl)methyl or alkyl;

-   each R¹⁸ is independently hydrogen or alkyl;-   each of R³⁷ and R³⁸ is independently chosen from hydrogen, methyl,    and (N,N-diethylcarbamoyl)methyl;-   R⁴¹ is (N,N-diethylcarbamoyl)methyl;-   R⁴² is chosen from hydrogen, ethyl, and    (N,N-diethylcarbamoyl)methyl; and-   each of the one or more compounds of Formulae (I), (II), (III),    (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxy    acetamide is present in the dosage form in an amount of less than    0.2% by weight based on total weight of the    (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, any one of the one or more compounds of Formulae(I), (II), (III), (IV), (V), (VI), (XIII), and (XV), andN,N-diethyl-2-hydroxy acetamide is present in the dosage form in anamount of less than 0.1% by weight based on total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formulae (I), (II),(III), (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide is present in a combined total amount of less than 3% byweight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formulae (I), (II),(III), (IV), (V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide is present in a combined total amount of less than 2% byweight based on total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formulae (I), (II),(III), (IV), (V), (VI), (XIII), and (XV) is selected from:

-   Formula (I) compounds    1,2-bis((N,N-diethylcarbamoyl)methoxycarbonyl)-3,4-bis(methoxycarbonyl)cyclobutane;    1,3-((N,N-diethylcarbamoyl)methoxycarbonyl)-2,4-bis(methoxycarbonyl)cyclobutane;    1-(N,N-diethylcarbamoyl)methoxycarbonyl-2-methoxycarbonylcyclobutane-3,4-dicarboxylic    acid;    1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,3-dicarboxylic    acid;    1,3-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,4-dicarboxylic    acid; 1,2-bis(methoxycarbonyl)cyclobutane-3,4-dicarboxylic acid;    1,3-bis(methoxycarbonyl)cyclobutane-2,4-dicarboylic acid;    cyclobutane-1,2,3,4-tetracarboxylic acid;    1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)-3-methoxycarbonylcyclobutane-4-carboxylic    acid; 1,2-bis(methoxycarbonyl)cyclobutane-3,4-dicarboxylic acid;    1,2-bis(methoxycarbonyl)-3-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-4-carboxylic    acid;    1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)-3-(methoxycarbonyl)cyclobutane-4-carboxylic    acid;    1-((N,N-diethylcarbamoyl)methoxycarbonyl)-2,3-bis(methoxycarbonyl)cyclobutane-4-carboxylic    acid;    1-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic    acid; and 1-(methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid;-   Formula (II) compounds    (N,N-diethylcarbamoyl)methyl-methyl-hydroxysuccinate;    methyl-hydroxysuccinic mono-acid;    (N,N-diethylcarbamoyl)methyl-hydroxysuccinic mono-acid;    hydroxysuccinic acid;    (N,N-diethylcarbamoyl)methyl-methyl-mercaptosuccinate;    methylmercaptosuccinic mono-acid;    (N,N-diethylcarbamoyl)methyl-mercaptosuccinic mono-acid;    mercaptosuccinic acid;    (N,N-diethylcarbamoyl)methyl-methyl-aminosuccinate;    methylaminosuccinic mono-acid;    (N,N-diethylcarbamoyl)methyl-aminosuccinic mono-acid; and    aminosuccinic acid;-   Formula (III) compounds cis-(N,N-diethylcarbamoyl)methyl-methyl    oxirane dicarboxylate; cis-(methoxycarbonyl)oxirane carboxylic    mono-acid; cis-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane    carboxylic mono-acid; cis-oxirane 2,3-dicarboxylic acid;    trans-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate;    trans-(methoxycarbonyl)oxirane carboxylic mono-acid;    trans-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylic    mono-acid; and trans-oxirane 2,3-dicarboxylic acid;-   Formula (IV) compounds    (N,N-diethylcarbamoyl)methyl-methyl-succinate; methylsuccinic    mono-acid; ((N,N-diethylcarbamoyl)methyl)succinic mono-acid; and    succinic acid;-   Formula (V) compounds    (N,N-diethylcarbamoyl)methyl-methyl-2,3-dihydroxysuccinate;    methyl-2,3-dihydroxysuccinic mono-acid;    (N,N-diethylcarbamoyl)methyl-2,3-dihydroxysuccinic mono-acid; and    2,3-dihydroxysuccinic acid (tartaric acid);-   Formula (VI) compounds wherein:

Q is —O—, and each R¹⁵ and R¹⁶ is methyl;

Q is —O—, and each R¹⁵ and R¹⁶ is H;

Q is —O—, and each R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —O—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —O—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —O—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —S—, and each of R¹⁵ and R¹⁶ is methyl;

Q is —S—, and each of R¹⁵ and R¹⁶ is H;

Q is —S—, and each of R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —S—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —S—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —S—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NH—, and each of R¹⁵ and R¹⁶ is methyl;

Q is —NH—, and each of R¹⁵ and R¹⁶ is H;

Q is —NH—, and each of R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NH—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —NH—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NH—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NMe—, and each of R¹⁵ and R¹⁶ is methyl;

Q is —NMe—, and each of R¹⁵ and R¹⁶ is H;

Q is —NMe—, and each of R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NMe—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —NMe—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NMe—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —CH₂—, and each R¹⁵ and R¹⁶ is methyl;

Q is —CH₂—, and each R¹⁵ and R¹⁶ is H;

Q is —CH₂—, and each R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —CH₂—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —CH₂—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl; and

Q is —CH₂—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

-   Formula (XIII) compounds (N,N-diethylcarbamoyl)methyl methyl    maleate, (N,N-diethylcarbamoyl)methyl maleic acid,    bis(N,N-diethylcarbamoyl)methyl maleate, dimethyl maleate, methyl    maleate, and maleic acid;-   Formula (XV) compounds    (2E)-3-(((N,N-diethylcarbamoyl)methyl)oxycarbonyl)prop-2-enoic acid;    (N,N-diethylcarbamoyl)methyl ethyl (2E)but-2-ene-1,4-dioate; and    bis(N,N-diethylcarbamoyl)methyl(2E)but-2-ene-1,4-dioate;-   isomers of any of the foregoing compounds and salts of any of the    foregoing compounds.

In some embodiments, the dosage form contains one or more compounds ofFormula (I), wherein the one or more compounds of Formula (I) are1R,2R,3S,4S-isomers. In some embodiments, the dosage form includes apharmaceutically acceptable vehicle. In some embodiments, thepharmaceutically acceptable vehicle is selected from a carrier, adiluent, an excipient, a wetting agent, an emulsifier, a buffer, astabilizer, a thickener, a lubricant, a coloring agent, and combinationsthereof. In some embodiments, the dosage form is in the form of a tabletor capsule.

In some embodiments, the dosage form contains a compound of Formula (I),comprising an opaque layer that is free of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the opaque layer is a coating. In some embodiments, theopaque layer comprises a gelatin capsule comprising an opaque material.In some embodiments, the dosage form is enclosed in a package thatlimits exposure of the dosage form to ambient light. In someembodiments, the package is a bottle comprising an opaque polymer. Insome embodiments, the package is a blister pack comprising metal foil,an opaque polymer or a combination thereof.

In some embodiments, the dosage form contains a compound of Formula(II), wherein the dosage form is substantially free of materials thatpromote addition reactions of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the dosage form issubstantially free of alcohols, mercaptans, alkylamines anddialkylamines. In some embodiments, the dosage form is substantiallyfree of R⁶OH, R⁶SH, R⁶NH₂, and R⁶N(H)R⁸; wherein each of R⁶ and R⁸ isalkyl.

In some embodiments, the dosage form contains a compound of Formula(III), wherein the dosage form is substantially free of PVP, PEG, andpolysorbate surfactant. In some embodiments, the dosage form containcompound of Formula (III), comprising an antioxidant, a free radicalscavenger or a combination thereof. In some embodiments, the one or morecompounds of Formula (III) comprises (N,N-diethylcarbamoyl)methyl methyloxirane-2,3-dicarboxylate.

In some embodiments, the dosage form contains a compound of Formula(IV), wherein the dosage form is substantially free of any compoundcapable of facilitating the reduction of the double bond of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the dosage form is substantially free of any compoundscontaining a hydrazino group.

In some embodiments, the dosage form contains a compound of Formula (V),comprising an antioxidant, a free radical scavenger or a combinationthereof.

In some embodiments, the dosage form contains a compound of Formula(VI), wherein the dosage form is substantially free of materials thatare capable of reacting with (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate to form Diels-Alder products. In someembodiments, the dosage form is substantially free of compoundscontaining cyclopentadiene, furan, thiophene, and pyrrole moieties.

In some embodiments, a method of treating a disease in a patientcomprises administering to the patient a dosage form as described above.In some embodiments, the disease is selected from multiple sclerosis andpsoriasis. In some embodiments, the disease is selected from adrenalleukodystrophy, AGE-induced genome damage, Alexander Disease, Alper'sDisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcott-Marie-Tooth Disease, childhoodataxia with central nervous system hypomyelination, chronic idiopathicperipheral neuropathy, chronic obstructive pulmonary disease, diabeticretinopathy, graft versus host disease, hepatitis C viral infection,herpes simplex viral infection, human immunodeficiency viral infection,Huntington's disease, irritable bowel disorder, ischemia, KrabbeDisease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, Zellweger's syndrome, granulomas includingannulaire, pemphigus, bollus pemphigoid, Behcet's disease, contactdermatitis, acute dermatitis, chronic dermatitis, alopecia areata(totalis and universalis), sarcoidosis, cutaneous sarcoidosis, pyodermagangrenosum, cutaneous lupus, Crohn's disease, and cutaneous Crohn'sdisease.

In a second aspect, a pharmaceutical dosage form for treating a diseasein a patient is provided, comprising:

-   (a) a therapeutically effective amount of Methyl    4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and-   (b) one or more compounds of Formulae (VII), (VIII), (IX), (X),    (XI), (XII), (XIV), or (XVI):

4-morpholin-4-ylbutan-1-ol,

-   and salts of any of the foregoing, wherein:-   each of R¹⁹ through R²² is independently chosen from hydrogen,    methyl, and 4-morpholin-4-ylbutyl;-   each R²³ and R²⁵ is independently chosen from hydrogen, methyl, and    4-morpholin-4-ylbutyl;-   Y is chosen from O, S, NH and NR²⁶;-   R²⁴ is chosen from hydrogen, lower alkyl, substituted lower alkyl,    aryl, and substituted aryl;-   R²⁶ is chosen from lower alkyl;-   each of R²⁷ and R²⁸ is independently chosen from hydrogen, methyl,    and 4-morpholin-4-ylbutyl;-   each of R²⁹ and R³⁹ is independently chosen from hydrogen, methyl,    and 4-morpholin-4-ylbutyl;-   each of R³¹ and R³² is independently chosen from hydrogen, methyl,    and 4-morpholin-4-ylbutyl;-   Q is —O—, —S—, —NH—, —N(R³⁵)—, or —C(R³⁶)₂—;-   each of R³³ and R³⁴ is independently chosen from hydrogen, methyl,    and 4-morpholin-4-ylbutyl;-   R³⁵ is 4-morpholin-4-ylbutyl or alkyl;-   each R³⁶ is independently hydrogen or alkyl;-   each of R³⁹ and R⁴⁰ is independently chosen from hydrogen, methyl,    and 4-morpholin-4-ylbutyl;-   R⁴³ is 4-morpholin-4-ylbutyl;-   R⁴⁴ is chosen from hydrogen, ethyl, and 4-morpholin-4-ylbutyl; and-   each of the one or more compounds of Formulae (VII), (VIII), (IX),    (X), (XI), (XII), (XIV), and (XVI), and 4-morpholin-4-ylbutan-1-ol    are present in the dosage form in an amount of less than 0.2% by    weight based on total weight of the methyl 4-morpholin-4-ylbutyl    (2E)but-2-ene-1,4-dioate.

In some embodiments, any one of the one or more compounds of Formulae(VII), (VIII), (IX), (X), (XI), (XII), (XIV), and (XVI), and4-morpholin-4-ylbutan-1-ol are present in the dosage form in an amountof less than 0.1% by weight based on total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formulae (VII),(VIII), (IX), (X), (XI), (XII), (XIV), and (XVI), and4-morpholin-4-ylbutan-1-ol are present in a combined total amount ofless than 3% by weight based on total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formulae (VII),(VIII), (IX), (X), (XI), (XII), (XIV), and (XVI), and4-morpholin-4-ylbutan-1-ol are present in a combined total amount ofless than 2% by weight based on total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formulae (VII),(VIII), (IX), (X), (XI), (XII), (XIV), and (XVI) are selected from:

-   Formula (VII) compounds    1,2-bis(methoxycarbonyl)-3,4-bis(4-morpholin-4-ylbutoxycarbonyl)cyclobutane;    1,3-bis(methoycarbonyl)-2,4-bis(4-morpholin-4-ylbutoxycarbonyl)cyclobutane;    1-methoxycarbonyl-2-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-3,4-dicarboxylic    acid; 1,2-bis(methoxycarbonyl)cyclobutane-2,3-dicarboxylic acid;    1,3-bis(methoxycarbonyl)cyclobutane-2,4-dicarboxylic acid;    1,2-bis-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-3,4-dicarboylic    acid; 1,3-bis-(4-morpholin-4-ylbutyl)cyclobutane-2,4-dicarboylic    acid; cyclobutane-1,2,3,4-tetracarboxylic acid;    1,2-bis(methoxycarbonyl)-3-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-4-carboxylic    acid;    1,2-bis-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-3,4-dicarboxylic    acid;    1,2-bis(4-morpholin-4-ylbutoxycarbonyl)-3-(methoxycarbonyl)cyclobutane-4-carboxylic    acid;    1,2-bis(methoxycarbonyl)-3-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-4-carboxylic    acid; 1-methoxycarbonyl-2,3-bis-(4-morpholin-4-ylbutoxycarbonyl)    cyclobutane-4-carboxylic acid;    1-(methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid; and    1-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-2,3,4-tricarboxylic    acid;-   Formula (VIII) compounds    methyl-(4-morpholin-4-ylbutyl)-hydroxysuccinate;    (4-morpholin-4-ylbutyl)-hydroxysuccinic mono-acid;    methylhydroxysuccinic mono-acid; hydroxysuccinic acid;    methyl-(4-morpholin-4-ylbutyl)-mercaptosuccinate;    (4-morpholin-4-ylbutyl)-mercaptosuccinic mono-acid;    methyl-mercaptosuccinic mono-acid; mercaptosuccinic acid;    methyl-(4-morpholin-4-ylbutyl)-aminosuccinate;    (4-morpholin-4-ylbutyl)-aminosuccinic mono-acid; methylaminosuccinic    mono-acid; and aminosuccinic acid;-   Formula (IX) compounds cis-methyl-(4-morpholin-4-ylbutyl)-oxirane    dicarboxylate; cis-(4-morpholin-4-ylbutoxycarbonyl)-oxirane    carboxylic mono-acid; cis-methoxycarbonyloxirane carboxylic    mono-acid; cis-oxirane 2,3-dicarboxylic acid;    trans-methyl-(4-morpholin-4-ylbutoxycarbonyl)-oxirane dicarboxylate;    trans-(4-morpholin-4-ylbutoxycarbonyl)-oxirane carboxylic mono-acid;    trans-(methoxycarbonyl)oxirane carboxylic mono-acid; and    trans-oxirane 2,3-dicarboxylic acid;-   Formula (X) compounds methyl-(4-morpholin-4-ylbutyl)-succinate;    (4-morpholin-4-ylbutyl)-succinic mono-acid; methylsuccinic    mono-acid; and succinic acid;-   Formula (XI) compounds    methyl-(4-morpholin-4-ylbutyl)-2,3-dihydroxysuccinate;    (4-morpholin-4-ylbutyl)-2,3-dihydroxysuccinic mono-acid;    methyl-2,3-dihydroxysuccinic mono-acid; and 2,3-dihydroxysuccinic    acid (tartaric acid);-   Formula (XII) compounds wherein:

Q is —O—, and each R³³ and R³⁴ is methyl;

Q is —O—, and each R³³ and R³⁴ is H;

Q is —O—, and each R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —O—, R³³ is H, and R³⁴ is methyl;

Q is —O—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —O—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —S—, and each of R³³ and R³⁴ is methyl;

Q is —S—, and each of R³³ and R³⁴ is H;

Q is —S—, and each of R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —S—, R³³ is H, and R³⁴ is methyl;

Q is —S—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —S—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NH—, and each of R³³ and R³⁴ is methyl;

Q is —NH—, and each of R³³ and R³⁴ is H;

Q is —NH—, and each of R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NH—, R³³ is H, and R³⁴ is methyl;

Q is —NH—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NH—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NMe—, and each of R³³ and R³⁴ is methyl;

Q is —NMe—, and each of R³³ and R³⁴ is H;

Q is —NMe—, and each of R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NMe—, R³³ is H, and R³⁴ is methyl;

Q is —NMe—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NMe—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —CH₂—, and each R³³ and R³⁴ is methyl;

Q is —CH₂—, and each R³³ and R³⁴ is H;

Q is —CH₂—, and each R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —CH₂—, R³³ is H, and R³⁴ is methyl;

Q is —CH₂—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl; and

Q is —CH₂—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

-   Formula (XIV) compounds 4-morpholin-4-ylbutyl methyl maleate,    4-morpholin-4-ylbutyl maleic acid, bis(4-morpholin-4-ylbutyl)    maleate, dimethyl maleate, methyl maleate, and maleic acid;-   Formula (XVI) compounds    (2E)-3-((4-morpholin-4-ylbutyl)oxycarbonyl)prop-2-enoic acid; ethyl    4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-diate; and    bis-(4-morpholin-4-ylbutyl) (2E)but-2-ene-1,4-dioate;-   isomers of any of the foregoing compounds and salts of any of the    foregoing compounds.

In some embodiments, the dosage form contains one or more compounds ofFormula (VII), wherein the one or more compounds of Formula (VII) are1R,2R,3S,4S-isomers. In some embodiments, the dosage form includes apharmaceutically acceptable vehicle. In some embodiments, thepharmaceutically acceptable vehicle is selected from a carrier, adiluent, an excipient, a wetting agent, an emulsifier, a buffer, astabilizer, a thickener, a lubricant, a coloring agent and combinationsthereof. In some embodiments, the dosage form is in the form of a tabletor capsule.

In some embodiments, the dosage form contains a compound of Formula(VII), comprising an opaque layer that is free of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theopaque layer is a coating. In some embodiments, the opaque layercomprises a gelatin capsule comprising an opaque material. In someembodiments, the dosage form is enclosed in a package that limitsexposure of the dosage form to ambient light. In some embodiments, thepackage is a bottle comprising an opaque polymer. In some embodiments,the package is a blister pack comprising metal foil, an opaque polymeror a combination thereof.

In some embodiments, the dosage form contains a compound of Formula(VIII), wherein the dosage form is substantially free of materials thatpromote addition reactions of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the dosage form issubstantially free of alcohols, mercaptans, alkylamines anddialkylamines. In some embodiments, the dosage form is substantiallyfree of R²⁴OH, R²⁴SH, R²⁴NH₂, and R²⁴N(H)R²⁶; wherein each of R²⁴ andR²⁶ is alkyl. In some embodiments, the dosage form contained a compoundof Formula (X), wherein the dosage form is substantially free of anycompound capable of facilitating the reduction of the double bond ofmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the dosage form is substantially free of any compoundscontaining a hydrazino group.

In some embodiments, the dosage form contains a compound of Formula(IX), wherein the dosage form is substantially free of PVP, PEG andpolysorbate surfactant. In some embodiments, the dosage form contains acompound of Formula (IX), comprising an antioxidant, a free radicalscavenger or a combination thereof. In some embodiments, the one or morecompounds of Formula (IX) comprises methyl 4-morpholin-4-ylbutyloxirane-2,3-dicarboxylate.

In some embodiments, the dosage form contains a compound of Formula(XI), comprising an antioxidant, a free radical scavenger or acombination thereof.

In some embodiments, the dosage form contained a compound of Formula(XII), wherein the dosage form is substantially free of materials thatare capable of reacting with methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate to form Diels-Alder products. In someembodiments, the dosage form is substantially free of compoundscontaining cyclopentadiene, furan, thiophene, and pyrrole moieties.

In some embodiments, a method of treating a disease in a patient isprovided, comprising administering to the patient a dosage form asdescribed above. In some embodiments, the disease is selected frommultiple sclerosis and psoriasis. In some embodiments, the disease isselected from adrenal leukodystrophy, AGE-induced genome damage,Alexander Disease, Alper's Disease, Alzheimer's disease, amyotrophiclateral sclerosis, angina pectoris, arthritis, asthma, balo concentricsclerosis, Canavan disease, cardiac insufficiency including leftventricular insufficiency, central nervous system vasculitis,Charcott-Marie-Tooth Disease, childhood ataxia with central nervoussystem hypomyelination, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, diabetic retinopathy, graftversus host disease, hepatitis C viral infection, herpes simplex viralinfection, human immunodeficiency viral infection, Huntington's disease,irritable bowel disorder, ischemia, Krabbe Disease, lichen planus,macular degeneration, mitochondrial encephalomyopathy, monomelicamyotrophy, multiple sclerosis, myocardial infarction, neurodegenerationwith brain iron accumulation, neuromyelitis optica, neurosarcoidosis,NF-κB mediated diseases, optic neuritis, paraneoplastic syndromes,Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateralsclerosis, progressive supranuclear palsy, psoriasis, reperfusioninjury, retinopathia pigmentosa, Schilder's Disease, subacutenecrotizing myelopathy, Susac's syndrome, transplantation rejection,transverse myelitis, a tumor, ulcerative colitis, Zellweger's syndrome,granulomas including annulaire, pemphigus, bollus pemphigoid, Behcet'sdisease, contact dermatitis, acute dermatitis, chronic dermatitis,alopecia areata (totalis and universalis), sarcoidosis, cutaneoussarcoidosis, pyoderma gangrenosum, cutaneous lupus, Crohn's disease andcutaneous Crohn's disease.

The compositions and dosage forms disclosed herein can be used to treatany number of diseases for which FAEs are known or thought to betherapeutically effective. In several aspects, the compositions anddosage forms disclosed herein can be used to treat multiple sclerosisand psoriasis.

Additional embodiments and features are set forth in part in thedescription that follows, and in part will become apparent to thoseskilled in the art upon examination of the specification, or may belearned by the practice of the embodiments discussed herein. A furtherunderstanding of the nature and advantages of certain embodiments may berealized by reference to the remaining portions of the specification andthe drawings, which forms a part of this disclosure.

Definitions

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is bonded through the carbon atom.

“Alkyl” refers to a saturated or unsaturated, branched, orstraight-chain, monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkene,or alkyne. Examples of alkyl groups include, but are not limited to,methyl; ethyls such as ethanyl, ethenyl, and ethynyl; propyls such aspropan-1-yl, propan-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such asbutan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds, and groupshaving combinations of single, double, and triple carbon-carbon bonds.Where a specific level of saturation is intended, the terms alkanyl,alkenyl, and alkynyl are used. In certain embodiments, an alkyl groupcan have from 1 to 20 carbon atoms (C₁₋₂₀) in certain embodiments, from1 to 10 carbon atoms (C₁₋₁₀), in certain embodiments from 1 to 8 carbonatoms (C₁₋₈), in certain embodiments, from 1 to 6 carbon atoms (C₁₋₆),in certain embodiments from 1 to 4 carbon atoms (C₁₋₄), and in certainembodiments, from 1 to 3 carbon atoms (C₁₋₃).

The term “alkyl” is specifically intended to include lower alkyl groups.As used herein, the phrase “lower alkyl” refers to a saturated orunsaturated, branched, or straight-chain, monovalent hydrocarbon radicalof six or fewer carbon atoms, derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane, alkene, or alkyne. Incertain embodiments, a lower alkyl group can have from 1 to 6 carbonatoms (C₁₋₆), in certain embodiments from 1 to 5 carbon atoms (C₁₋₅), incertain embodiments from 1 to 4 carbon atoms (C₁₋₄), in certainembodiments, from 1 to 3 carbon atoms (C₁₋₃), in certain embodimentsfrom 1 to 2 carbon atoms (C₁₋₂) and in certain embodiments a singlecarbon atom. Examples of lower alkyl groups include, but are not limitedto, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl,n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl,etc., and the like.

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl benzene; bicyclic ring systems wherein atleast one ring is carbocyclic and aromatic, for example, naphthalene,indane, and tetralin; and tricyclic ring systems wherein at least onering is carbocyclic and aromatic, for example, fluorene. Arylencompasses multiple ring systems having at least one carbocyclicaromatic ring fused to at least one carbocyclic aromatic ring,cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes aphenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containingone or more heteroatoms chosen from N, O, and S. For such fused,bicyclic ring systems wherein only one of the rings is a carbocyclicaromatic ring, the radical carbon atom may be at the carbocyclicaromatic ring or at the heterocycloalkyl ring. Examples of aryl groupsinclude, but are not limited to, groups derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexalene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like. In certain embodiments, an aryl group can have from 6 to20 carbon atoms (C₆₋₂₀), from 6 to 12 carbon atoms (C₆₋₁₂), from 6 to 10carbon atoms (C₆₋₁₀), and in certain embodiments from 6 to 8 carbonatoms (C₆₋₈). Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined herein.

“Compounds” refers to chemical substances consisting of two or moredifferent chemical elements that can be separated into simplersubstances by chemical reactions. Compounds have a unique and definedchemical structure; they consist of a fixed ratio of atoms that are heldtogether in a defined spatial arrangement by chemical bonds. Compoundsinclude any specific compounds within a given chemical formula.Compounds may be identified either by their chemical structure and/orchemical name. Compounds are named using Chemistry 4-D Draw Pro, version7.01c (ChemInnovation Software, Inc., San Diego, Calif.). When thechemical structure and chemical name conflict, the chemical structure isdeterminative of the identity of the compound. The compounds describedherein may comprise one or more chiral centers and/or double bonds andtherefore may exist as stereoisomers such as double-bond isomers (i.e.,geometric isomers), enantiomers, or diastereomers. Accordingly, anychemical structures within the scope of the specification depicted, inwhole or in part, with a relative configuration encompasses all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures may be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.Compounds include, but are not limited to, optical isomers, racemates,and other mixtures. In such embodiments, a single enantiomer ordiastereomer, i.e., optically active form can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematesmay be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatographyusing, for example, chiral stationary phases. Notwithstanding theforegoing, in the compounds monomethyl fumarate, dimethyl fumarate, and(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate, the configuration of theillustrated double bond is only in the E configuration (i.e. transconfiguration).

Compounds may also exist in several tautomeric forms including the enolform, the keto form, and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofany illustrated compounds. Compounds also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds disclosed herein include, but arenot limited to, ²H, 3H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. In general, compounds as referred to herein maybe free acid, hydrated, solvated, or N-oxides. Compounds may exist inone or more ionic forms. Certain compounds may exist in multiplecrystalline, co-crystalline, or amorphous forms. Compounds includepharmaceutically acceptable salts, or pharmaceutically acceptablesolvates of the free acid form of any of the foregoing, as well ascrystalline forms of any of the foregoing.

Compounds also include solvates. A solvate refers to a molecular complexof a compound with one or more solvent molecules in a stoichiometric ornon-stoichiometric amount. Such solvent molecules are those commonlyused in the pharmaceutical art, which are known to be innocuous to apatient, e.g., water, ethanol, and the like. A molecular complex of acompound or moiety of a compound and a solvent can be stabilized bynon-covalent intra-molecular forces such as, for example, electrostaticforces, van der Waals forces, or hydrogen bonds. The term “hydrate”refers to a solvate in which the one or more solvent molecules is water.

Further, when partial structures of compounds are illustrated, anasterisk (*) indicates the point of attachment of the partial structureto the rest of the molecule. “Dimethyl fumarate” refers to the dimethylester of fumaric acid. The compound has a molecular weight of 144.13daltons and the following chemical structure:

This compound is also known by the names Dimethyl (E)-butenedioate(IUPAC), trans-1,2-Ethylenedicarboxylic acid dimethyl ester and(E)-2-Butenedioic acid dimethyl ester. The compound is also referred toby the acronym DMF. DMF can be synthesized according to the methodsdescribed in Chinese Patent Publication CN 101318901A, the disclosuresof which are incorporated herein by reference.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Drug” as defined under 21 U.S.C. § 321(g)(1) means (A) articlesrecognized in the official United States Pharmacopoeia, officialHomeopathic Pharmacopoeia of the United States, or official NationalFormulary, or any supplement to any of them; and (B) articles intendedfor use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease in man or other animals; and (C) articles (other than food)intended to affect the structure or any function of the body of man orother animals.

“Monomethyl fumarate” refers to the monomethyl ester of fumaric acid.The compound has a molecular weight of 130.10 daltons and the followingchemical formula:

The compound is also commonly referred to as 2(E)-Butenedioic acid1-methyl ester; (2E)-4-Methoxy-4-oxobut-2-enoic acid; Fumaric acidhydrogen 1-methyl ester; (2E)-2-Butenedioic acid 1-methyl ester;(E)-2-Butenedioic acid monomethyl ester; Monomethyltrans-ethylene-1,2-dicarboxylate; and methyl hydrogen fumarate. Thecompound is also referred to herein and elsewhere by the acronyms MMFand/or MHF. MMF can be synthesized according to the methods described inDymicky, Preparation of Monomethyl Fumarate, Organic Preparations andProcedures International: The New Journal for Organic Synthesis, Vol 14,Issue 4, 1983; and Spatz et al., J. Org. Chem., 1958, 23 (10),1559-1560.

“Multiple sclerosis” also known as “disseminated sclerosis” or“encephalomyelitis disseminata”, and sometimes referred to by theacronym MS, is an inflammatory disease in which the fatty myelin sheathsaround the axons of the brain and spinal cord are damaged, leading todemyelination and scarring as well as a broad spectrum of signs andsymptoms. Disease onset usually occurs in young adults, and it is morecommon in women. It has a prevalence that ranges between 2 and 150 per100,000.

MS affects the ability of nerve cells in the brain and spinal cord tocommunicate with each other effectively. Nerve cells communicate bysending electrical signals called action potentials down long fiberscalled axons, which are contained within an insulating substance calledmyelin. In MS, the body's own immune system attacks and damages themyelin. When myelin is lost, the axons can no longer effectively conductsignals. The name multiple sclerosis refers to scars (sclerae-betterknown as plaques or lesions) particularly in the white matter of thebrain and spinal cord, which is mainly composed of myelin. Although muchis known about the mechanisms involved in the disease process, the causeremains unknown. Theories include genetics or infections. Differentenvironmental risk factors have also been found.

Almost any neurological symptom can appear with the disease, and thedisease often progresses to physical and cognitive disability. MS takesseveral forms, with new symptoms occurring either in discrete attacks(relapsing forms) or accumulating over time (progressive forms). Betweenattacks, symptoms may go away completely, but permanent neurologicaldeficits often occur, especially as the disease advances.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; andsalts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine, andthe like. In certain embodiments, a pharmaceutically acceptable salt isthe hydrochloride salt. In certain embodiments, a pharmaceuticallyacceptable salt is the sodium salt.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient,which does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Pharmaceutical composition” refers to a therapeutically active compoundand at least one pharmaceutically acceptable vehicle, with which thecompound is administered to a patient.

“Polyethylene glycol” and “PEG” each refer to a linear polymer formed bythe addition reaction of ethylene glycol with ethylene oxide. PEG iscommercially available in average molecular weights ranging from about200 to greater than 20,000. The commercially available grades ofpolyethylene glycol are marketed based on the average molecular weight,e.g., the grade nomenclature is identified with the molecular weight.For example, PEG 400 represents material with an average molecularweight of 400 and the material with an average molecular weight of 600is known as PEG 600. PEG 200, 300, 400, and 600 are clear viscousliquids at room temperature; PEG 900, 1000, 1450, 3350, 4500 and 8000are white, waxy solids.

“Polyvinylpyrrolidone” and “PVP” each refer to a linear polymer of1-vinyl-2-pyrrolidone. PVP, also known as Povidone, is commerciallyavailable as a series of products having mean molecular weights rangingfrom about 10,000 to about 700,000. The various products are marketedaccording to average molecular weights designated K-values; e.g., GAFCorporation supplies PVP having K-value=15 as having an averagemolecular weight of about 10,000, and K-value=30 as having an averagemolecular weight of about 40,000.

“Psoriasis” is an immune-mediated disease that affects the skin. It istypically a lifelong condition. Psoriasis occurs when the immune systemmistakes a normal skin cell for a pathogen, and sends out faulty signalsthat cause overproduction of new skin cells. There are five types ofpsoriasis: plaque, guttate, inverse, pustular, and erythrodermic. Themost common form, plaque psoriasis, is commonly seen as red and whitehues of scaly patches appearing on the top first layer of the epidermis(skin). Some patients, though, have no dermatological signs or symptoms.The name psoriasis is from the Greek word, meaning roughly “itchingcondition” (psora “itch”+-sis “action, condition”).

In plaque psoriasis, skin rapidly accumulates at these sites, whichgives it a silvery-white appearance. Plaques frequently occur on theskin of the elbows and knees, but can affect any area, including thescalp, palms of hands and soles of feet, and genitals. In contrast toeczema, psoriasis is more likely to be found on the outer side of thejoint.

The disorder is a chronic recurring condition that varies in severityfrom minor localized patches to complete body coverage. Fingernails andtoenails are frequently affected (psoriatic nail dystrophy) and can beseen as an isolated sign. Psoriasis can also cause inflammation of thejoints, which is known as psoriatic arthritis. Between 10% and 30% ofall people with psoriasis also have psoriatic arthritis.

The cause of psoriasis is not fully understood, but it is believed tohave a genetic component and local psoriatic changes can be triggered byan injury to the skin known as the Koebner phenomenon. Variousenvironmental factors have been suggested as aggravating to psoriasis,including oxidative stress, stress, withdrawal of systemiccorticosteroid, as well as other environmental factors, but few haveshown statistical significance.

“Treating” or “treatment” of any disease refers to reversing,alleviating, arresting, or ameliorating a disease or at least one of theclinical symptoms of a disease, reducing the risk of acquiring a diseaseor at least one of the clinical symptoms of a disease, inhibiting theprogress of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter that may or may not be discernible to thepatient. In certain embodiments, “treating” or “treatment” refers todelaying the onset of the disease or at least one or more symptomsthereof in a patient which may be exposed to or predisposed to a diseaseeven though that patient does not yet experience or display symptoms ofthe disease.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. The “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, severity of the disease and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

DETAILED DESCRIPTION

Reference is now made in detail to certain embodiments of pharmaceuticalcompositions of monomethyl fumarate. The disclosed embodiments are notintended to be limiting of the claims. To the contrary, the claims areintended to cover all alternatives, modifications, and equivalents.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate

Regulatory authorities worldwide require the amounts of impurities to bemaintained at the lowest possible levels in pharmaceutical compositionsand formulations. Hence there exists a need for stabilized compositionsof (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

If exposed to sufficient amounts of light or if sufficiently exposed toan oxidant, (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateis prone to a number of reactions such as oxidative stress andphotodegradation, which gives rise to impurities. Two of severalimpurities which can be generated are tetramethylcyclobutane-1,2,3,4-tetracarboxylate formed by photodegradation of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate anddimethyl oxirane-2,3-dicarboxylate formed by oxidation of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In a first aspect, a dosage form is provided which comprises (a) atherapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; (b) one or more cyclobutane compounds ofFormula (I):

and salts of any of the foregoing, wherein:

each of R¹ through R⁴ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl; and

wherein the one or more compounds of Formula (I) are present in a totalcombined amount of less than 2% by weight based on total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; and (c) apharmaceutically acceptable vehicle.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (I) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of less than about1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of less than about 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of less than about1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of less than about 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of less than about1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of less than about0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of less than about 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of less than about0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (I) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of about 0.001% to1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of about 0.001% to1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of about 0.001% to 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of about 0.001% to1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of about 0.001% to0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a combined total amount of about 0.001% to0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (I) are present in acombined total amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (I) arepresent in a total combined amount of less than about 2% by weight basedon total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (I) are present in a total combined amount of less than about1% by weight based on total weight of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (I) include tetramethylcyclobutane-1,2,3,4-tetracarboxylate, in which R¹ through R⁴ are allmethyl; 3,4-bis(methoxycarbonyl)cyclobutane-1,2-dicarboxylic acid, inwhich R¹ and R² are each hydrogen and R³ and R⁴ are each methyl;2,4-bis(methoxycarbonyl)cyclobutane-1,3-dicarboxylic acid, in which R¹and R³ are each hydrogen and R² and R⁴ are each methyl; andcyclobutane-1,2,3,4-tetracarboxylic acid, in which R¹ through R⁴ are allhydrogen; as well as and salts of any of the foregoing. In someembodiments, the one or more compounds of Formula (I) is selected fromthe group consisting of1,2-bis((N,N-diethylcarbamoyl)methoxycarbonyl)-3,4-bis(methoxycarbonyl)cyclobutane;1,3-((N,N-diethylcarbamoyl)methoxycarbonyl)-2,4-bis(methoxycarbonyl)cyclobutane;1-(N,N-diethylcarbamoyl)methoxycarbonyl-2-methoxycarbonylcyclobutane-3,4-dicarboxylicacid;1,24(N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,3-dicarboxylicacid;1,3-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,4-dicarboxylicacid; 1,2-bis(methoxycarbonyl)cyclobutane-3,4-dicarboxylic acid;1,3-bis(methoxycarbonyl)cyclobutane-2,4-dicarboylic acid;cyclobutane-1,2,3,4-tetracarboxylic acid;1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)-3-methoxycarbonylcyclobutane-4-carboxylicacid; 1,2-bis(methoxycarbonyl)cyclobutane-3,4-dicarboxylic acid;1,2-bis(methoxycarbonyl)-3-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-4-carboxylicacid;1,2-((N,N-diethylcarbamoyl)methoxycarbonyl)-3-(methoxycarbonyl)cyclobutane-4-carboxylicacid;1-((N,N-diethylcarbamoyl)methoxycarbonyl)-2,3-bis(methoxycarbonyl)cyclobutane-4-carboxylicacid;1-((N,N-diethylcarbamoyl)methoxycarbonyl)cyclobutane-2,3,4-tricarboxylicacid; and 1-(methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid; aswell as salts of any of the foregoing.

In some embodiments, the isomers of compounds of Formula (I) include,1R,2R,3R,4R-, 1S,2S,3S,4S-, 1R,2R,3S,4S-, or 1R,2S,3R,4S-isomers.

In some embodiments, the compounds of Formula (I) include1R,2R,3S,4S-isomers.

In some embodiments, each of the one or more compounds of Formula (I) ispresent in an amount of less than about 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (I) is present in an amount of less than about 0.2%by weight based on the total weight of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate. In some embodiments, each of the one ormore compounds of Formula (I) is present in an amount of less than about0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (I) is presentin an amount of less than about 0.1% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, each of the one or more compounds of Formula (I) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (I) ispresent in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (I) is present in an amount of about 0.001% to 0.2%by weight based on the total weight of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate. In some embodiments, each of the one ormore compounds of Formula (I) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (I) is presentin an amount of about 0.001% to 0.1% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, each of the one or more compounds of Formula (I) ispresent in an amount of about 0.001% to 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In order to maintain a low content of photodegradant compounds ofFormula (I) in a (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical composition or dosageform, the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateactive pharmaceutical ingredient as well as the dosage form should bothbe manufactured with minimal exposure to visible and/or UV light. Thus,(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate powdershould be exposed to visible and UV light levels below these limits inorder to maintain the levels of photodegradant compounds of Formula (I)within acceptable ranges.

In order to reduce the impact of light, including natural light,ultra-violet light and near-UV light, on the stability of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in a(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate-containingdosage form, a barrier layer or coating can be applied to the dosageform. For oral dosage forms, examples include a coating on a(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate-containingtablet or an opaque capsule containing (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioateparticles or pellets.

In some embodiments, the tablet or capsule coating is opaque and has athickness of at least 10 μm. In some embodiments, the coating has athickness of at least 300 μm. The coating may comprise a filler and/or apolymer. The coating may comprise an iron oxide colorant and otherexcipients. Alternatively, the coating may comprise a colorant (e.g.,FD&C Yellow #6, Sunset Yellow, or FD&C Red #40 Allura Red) and otherknown coating excipients. Alternatively, the coating may comprisetitanium dioxide, silicon dioxide or zinc dioxide and other knowncoating excipients.

The use of opaque plastic (e.g., high density polyethylene) pillbottles, e.g., with child-resistant screw caps, is one option to limitthe amount of light exposure to a (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing dosage form. Blister packs, a termused for several types of pre-formed plastic pharmaceutical packaging,is another option. The primary component of a blister pack is a cavityor pocket made from a formable web, usually a thermoformed plastic. Thisusually has a backing of paperboard or a lidding seal of aluminum foilor plastic. The plastics can be made opaque, and/or with an anti-UVlight coating, to limit the amount of light exposure to the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate dosageform.

In a second aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) one or more succinate compounds ofFormula (II):

and salts of any of the foregoing, wherein:

each of R⁵ and R⁷ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl;

Y is chosen from O, S, NH and NR⁸;

R⁶ is chosen from hydrogen, lower alkyl and aryl; and

R⁸ is chosen from lower alkyl.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, each of R⁶ and R⁸ is independently unsubstitutedalkyl. In some embodiments, each of R⁶ and R⁸ is independently alkyl,substituted with hydroxy.

In some embodiments, the one or more compounds of Formula (II) arepresent in a total combined amount of less than 3 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (II) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (II) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (II) arepresent in a combined total amount of less than about 3% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of less thanabout 2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of less than about 1.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of less thanabout 1.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or morecompounds) of Formula (II) are present in a combined total amount ofless than about 1.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of less than about 1.0% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of less thanabout 0.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of less than about 0.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of less thanabout 0.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (II) arepresent in a combined total amount of about 0.001% to 3% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of about 0.001%to 2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of about 0.001% to 1.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of about 0.001%to 1.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of about 0.001% to 1.0% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of about 0.001%to 0.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of about 0.001% to 0.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of about 0.001%to 0.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (II) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (II) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (II) include the following:(N,N-diethylcarbamoyl)methyl-methyl-hydroxysuccinate;methyl-hydroxysuccinic mono-acid;(N,N-diethylcarbamoyl)methyl-hydroxysuccinic mono-acid; hydroxysuccinicacid; (N,N-diethylcarbamoyl)methyl-methyl-mercaptosuccinate;methylmercaptosuccinic mono-acid;(N,N-diethylcarbamoyl)methyl-mercaptosuccinic mono-acid;mercaptosuccinic acid;(N,N-diethylcarbamoyl)methyl-methyl-aminosuccinate; methylaminosuccinicmono-acid; (N,N-diethylcarbamoyl)methyl-aminosuccinic mono-acid; andaminosuccinic acid; as well as salts of any of the foregoing.

In some embodiments, each of the one or more compounds of Formula (II)is present in an amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (II) is present in an amount of less than about0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (II) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (II) is present in an amount of less than about0.05% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (II)is present in an amount of about 0.001% to 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (II) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (II) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (II) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no alkanols or alcohols,thioalkanols or alkyl mercaptans, alkylamines, dialkylamines or anycompound capable of acting as a nucleophile for addition to the doublebond of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.For example, use of alcohols in a pharmaceutical composition can formthe 2-alkoxy compound (Formula II, —Y—R⁶ is —O-alkyl) impurities intothe formulation. Similarly, use of thioalcohols or mercaptans in apharmaceutical composition can form the 2-thioalkoxy compound (FormulaII, —Y—R⁶ is —S-alkyl) impurities into the formulation. Furthermore, useof primary amines in a pharmaceutical composition can form the2-alkylamino compound (Formula II, —Y—R⁶ is —NH-alkyl) impurities intothe formulation. Moreover, use of secondary amines in a pharmaceuticalcomposition can form the 2-dialkylamino compound (Formula II, —Y—R⁶ is—N(alkyl)₂) impurities into the formulation.

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of any alcohols,mercaptans, alkylamines, or dialkylamines. In some embodiments, thepharmaceutical compositions and dosage forms disclosed herein aresubstantially free of methanol, ethanol, methyl mercaptan, ethylarnine,propylamine, butylarnine, aspartame, diethanolamine, meglumine,monoethanolamine, or triethanolamine.

In a third aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) an oxirane compound of Formula (III):

and salts of any of the foregoing, wherein:

each of R⁹ and R¹⁰ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl; and

wherein the one or more compounds of Formula (III) are present in thedosage form in a combined total amount of less than 3% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate

In a third aspect, a dosage form is provided which comprises (a)(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; and (b) anoxirane compound of Formula (III):

and salts of any of the foregoing, wherein:

each of R⁹ and R¹⁰ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl; and

wherein the one or more compounds of Formula (III) are present in thedosage form in a combined total amount of less than 3% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate

In some embodiments of the pharmaceutical compositions and/or dosageforms, the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateis solid. In some embodiments of the pharmaceutical compositions and/ordosage forms, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is crystalline. In some embodiments of thepharmaceutical compositions and/or dosage forms, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate isamorphous.

In some embodiments, the one or more compounds of Formula (III) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (III) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (III) arepresent in a combined total amount of less than about 3% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of less thanabout 2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of less than about 1.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of less thanabout 1.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or morecompounds) of Formula (III) are present in a combined total amount ofless than about 1.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of less than about 1.0% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of less thanabout 0.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of less than about 0.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of less thanabout 0.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (III) arepresent in a combined total amount of about 0.001% to 3% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of about 0.001%to 2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of about 0.001% to 1.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of about 0.001%to 1.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of about 0.001% to 1.0% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of about 0.001%to 0.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of about 0.001% to 0.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of about 0.001%to 0.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (III) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (III) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl) methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments of the pharmaceutical compositions and/or dosage forms, theone or more compounds of Formula (III) include the following: dimethyloxirane-2,3-dicarboxylate (compound (2)), in which both R⁹ and R¹⁰ aremethyl; 3-(methoxycarbonyl)oxirane-2-carboxylic acid, in which R⁹ ismethyl and R¹⁰ is hydrogen; oxirane-2,3-dicarboxylic acid, in which bothR⁹ and R¹⁰ are hydrogen; and salts of any of the foregoing.

In some embodiments, each of the one or more compounds of Formula (III)is present in an amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (III) is present in an amount of less than about0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (III) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (III) is present in an amount of less than about0.05% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (III)is present in an amount of about 0.001% to 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (III) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (III) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (III) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments of the pharmaceutical compositions and/or dosageforms, the one or more compounds of Formula (III) comprise dimethyloxirane-2,3-dicarboxylate, and salts of any of the foregoing. In someembodiments of the pharmaceutical compositions and/or dosage forms, theone or more compounds of Formula (III) comprise dimethyloxirane-2,3-dicarboxylate. In other embodiments, the one or morecompounds of Formula (III) are selected from the group consisting ofcis-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate;cis-(methoxycarbonyl)oxirane carboxylic mono-acid;cis-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylic mono-acid;cis-oxirane 2,3-dicarboxylic acid;trans-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate;trans-(methoxycarbonyl)oxirane carboxylic mono-acid;trans-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylicmono-acid; and trans-oxirane 2,3-dicarboxylic acid; as well as salts ofany of the foregoing.

The toxicity of dimethyl oxirane-2,3-dicarboxylate was evaluated usingDerek Nexus version 2.0 (Lhasa Ltd., Leeds, UK) which predicts toxicitybased on a combination of published reports as well as compoundstructural characteristics and provides one of seven possible grades fortoxicity: certain, probable, plausible, equivocal, doubted, improbableand impossible. Although there are no published reports testing thetoxicity of compound (2), due to the epoxide portion of the molecule,the Derek Nexus database rates the toxicity of compound (2) as“plausible” meaning that the weight of evidence supports the propositionthat the compound is toxic.

Compound (2) and its NMR spectrum are shown in Example 1 of Habich etal. U.S. Pat. No. 4,863,916, the disclosures of which are incorporatedherein by reference. Using established analytical chemistry techniques,together with the disclosures in the Habich et al. patent, those skilledin the art can test pharmaceutical compositions and dosage forms for thepresence of compound (2).

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no polyvinylpyrrolidone(PVP) or polyethylene glycol (PEG). Use of polyvinylpyrrolidone (PVP) ina pharmaceutical composition can introduce peroxide impurities into theformulation since the PVP polymerization process involves the use ofpolymerization initiators such as peroxides, ozone, and hydrogenperoxides. Upon heat or light exposure, even trace amounts of peroxidescan decompose into free radicals, which can powerfully catalyzephotochemical reactions. Light-induced decomposition of polyoxyethylenechains of polyethylene glycols (PEG) or polysorbate surfactants can alsoresult in the formation of hydrogen peroxides and/or peroxide-freeradicals, which can promote degradation of (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of anypolyvinylpyrrolidone, polyethylene glycol and/or polysorbate surfactant.In some embodiments, the pharmaceutical compositions and dosage formsdisclosed herein contain no polyvinylpyrrolidone, polyethylene glycoland/or polysorbate surfactant.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein may comprise an antioxidant. Suitableantioxidants include methyl paraben and propyl paraben and their salts(such as sodium, potassium), vitamin E, vitamin E TPGS, propyl gallate,sulfites, ascorbic acid, sodium benzoate, citric acid, cyclodextrins,peroxide scavengers, benzoic acid, ethylenediaminetetraacetic acid(EDTA) and salts thereof, chain terminators (e.g., thiols and phenols),butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and thelike, and combinations of any of the foregoing. In some embodiments,antioxidants such as butylated hydroxytoluene (BHT) and butylatedhydroxyanisole (BHA) can be used. In some embodiments, the antioxidantmay be present in an amount of about from 0.01 to 5.0%, and in someembodiments about from 0.5 to 2.0% by weight of the total pharmaceuticalcomposition.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein may comprise an antioxidant. Suitable freeradical scavengers include tocopherol, naringenin and the like, andmixtures thereof.

In another aspect, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms comprise one or more vehicles or other excipients that arelow in oxidizing agents such as hydrogen peroxide, formaldehydes andformic acid and low in metallic impurities such as iron ions (e.g.,Fe⁺²) that have the capability to oxidize (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.

In a fourth aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) one or more succinate compounds ofFormula (IV):

and salts of any of the foregoing, wherein:

each of R¹¹ and R¹² is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (IV) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (IV) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (IV) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of less than about 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of less thanabout 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of less than about 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of less thanabout 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of less than about 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of less thanabout 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (IV) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of about 0.001%to 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of about 0.001% to 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of about 0.001%to 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IV) are present in a combined total amount of about 0.001%to 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IV) are present in acombined total amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

Compounds of Formula (IV) include the following: dimethyl succinate inwhich both R¹¹ and R¹² are methyl; 4-methoxy-4-oxobutanoic acid in whichR¹¹ is methyl and R¹² is hydrogen; succinic acid in which both R¹¹ andR¹² are hydrogen; and salts of any of the foregoing. In someembodiments, the one or more compounds of Formula (IV) are selected fromthe group consisting of (N,N-diethylcarbamoyl)methyl-methyl-succinate;methylsuccinic mono-acid; ((N,N-diethylcarbamoyl)methyl)succinicmono-acid; and succinic acid; as well as any salts thereof.

In some embodiments, each of the one or more compounds of Formula (IV)is present in an amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (IV) is present in an amount of less than about0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (IV) ispresent in an amount of less than about 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (IV) is present in an amount of less than about0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (IV) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (IV)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (IV) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (IV) ispresent in an amount of about 0.001% to 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (IV) is present in an amount of about 0.001% to0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compound of Formula (IV) is presentin an amount of about 0.001% to 0.05% by weight based on the totalweight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no compound(s) capableof forming (N,N-diethylcarbamoyl) methyl, hydrogen or hydrogen radicalswhich will, in turn, facilitate the reduction of the double bond of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of any compoundscontaining hydrazino group.

In a fifth aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) one or more succinate compounds ofFormula (V):

and salts of any of the foregoing wherein:

each of R¹³ and R¹⁴ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl) methyl.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (V) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (V) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (V) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of less than about1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of less than about 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of less than about1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of less than about 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of less than about1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of less than about0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of less than about 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of less than about0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (V) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of about 0.001% to1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of about 0.001% to1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of about 0.001% to 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of about 0.001% to1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of about 0.001% to0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (V) are present in a combined total amount of about 0.001% to0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (V) are present in acombined total amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

Compounds of Formula (V) include the following: 2,3-dihydroxysuccinicacid dimethyl ester, in which both R¹³ and R¹⁴ are methyl;2,3-dihydroxysuccinic acid monomethyl ester, in which R¹³ is methyl andR¹⁴ is hydrogen; 2,3-dihydroxysuccinic acid, in which both R¹³ and R¹⁴are hydrogen; and salts of any of the foregoing. In some embodiments,the one or more compound of Formula (V) are selected from the groupconsisting of(N,N-diethylcarbamoyl)methyl-methyl-2,3-dihydroxysuccinate;methyl-2,3-dihydroxysuccinic mono-acid;(N,N-diethylcarbamoyl)methyl-2,3-dihydroxysuccinic mono-acid; and2,3-dihydroxysuccinic acid (tartaric acid); as well as any saltsthereof.

In some embodiments, each of the one or more compounds of Formula (V) ispresent in an amount of less than about 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (V) is present in an amount of less than about 0.2%by weight based on the total weight of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate. In some embodiments, each of the one ormore compounds of Formula (V) is present in an amount of less than about0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (V) is presentin an amount of less than about 0.1% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, each of the one or more compounds of Formula (V) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (V) ispresent in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (V) is present in an amount of about 0.001% to 0.2%by weight based on the total weight of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate. In some embodiments, each of the one ormore compounds of Formula (V) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (V) is presentin an amount of about 0.001% to 0.1% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, each of the one or more compounds of Formula (V) ispresent in an amount of about 0.001% to 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no compound(s) capableof isomerizing the double bond of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain antioxidants and/or free radicalscavengers.

In a sixth aspect, a dosage form is provided which comprises (a)(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; and (b)one or more compounds of Formula (VI):

and salts of any of the foregoing, wherein:

Q is —O—, —S—, —NH—, —N(R¹⁷)— or C(R¹⁸)₂;

each of R¹⁵ and R¹⁶ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl;

R¹⁷ is (N,N-diethylcarbamoyl)methyl or alkyl; and

each R¹⁸ is independently hydrogen or alkyl; and

(c) a pharmaceutically acceptable vehicle.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (VI) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VI) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VI) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of less than about 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of less thanabout 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of less than about 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of less thanabout 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of less than about 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of less thanabout 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VI) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of about 0.001%to 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of about 0.001% to 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of about 0.001%to 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VI) are present in a combined total amount of about 0.001%to 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VI) are present in acombined total amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

Compounds of Formula (VI) include the following compounds, wherein:

Q is —O—, and each R¹⁵ and R¹⁶ is methyl;

Q is —O—, and each R¹⁵ and R¹⁶ is H;

Q is —O—, and each R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —O—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —O—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —O—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —S—, and each of R¹⁵ and R¹⁶ is methyl;

Q is —S—, and each of R¹⁵ and R¹⁶ is H;

Q is —S—, and each of R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —S—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —S—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —S—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NH—, and each of R¹⁵ and R¹⁶ is methyl;

Q is —NH—, and each of R¹⁵ and R¹⁶ is H;

Q is —NH—, and each of R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NH—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —NH—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NH—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NMe—, and each of R¹⁵ and R¹⁶ is methyl;

Q is —NMe—, and each of R¹⁵ and R¹⁶ is H;

Q is —NMe—, and each of R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NMe—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —NMe—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —NMe—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —CH₂—, and each R¹⁵ and R¹⁶ is methyl;

Q is —CH₂—, and each R¹⁵ and R¹⁶ is H;

Q is —CH₂—, and each R¹⁵ and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

Q is —CH₂—, R¹⁵ is H, and R¹⁶ is methyl;

Q is —CH₂—, R¹⁵ is H, and R¹⁶ is (N,N-diethylcarbamoyl)methyl; and

Q is —CH₂—, R¹⁵ is methyl, and R¹⁶ is (N,N-diethylcarbamoyl)methyl;

isomers of any of the foregoing compounds and salts of any of theforegoing compounds.

In some embodiments, each of the one or more compounds of Formula (VI)is present in an amount of less than about 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VI) is present in an amount of less than about0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VI) ispresent in an amount of less than about 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VI) is present in an amount of less than about0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VI) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (VI)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VI) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VI) ispresent in an amount of about 0.001% to 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VI) is present in an amount of about 0.001% to0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VI) ispresent in an amount of about 0.001% to 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In another aspect, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no compound(s) capableof reacting with (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioateto form Diels-Alder products.

For example, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate, which can act as dienophile, will react withcyclopentadiene, furan, thiofurans, or pyrroles, to form Diels-Aldercyclization products as shown below, where Q, R¹⁵ and R¹⁶ are as definedherein:

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of any compoundscontaining furan, thiophene, and pyrrole moieties.

In a thirteenth aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) one or more maleate compounds ofFormula (XIII):

and salts of any of the foregoing, wherein: each of R³⁷ and R³⁸ isindependently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (XIII) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIII) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIII) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of less than about 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of less thanabout 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of less than about 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of less thanabout 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of less than about 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of less thanabout 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIII) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of about 0.001%to 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of about 0.001% to 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of about 0.001%to 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIII) are present in a combined total amount of about 0.001%to 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIII) are present ina combined total amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIII) areselected from the group consisting of (N,N-diethylcarbamoyl)methylmethyl maleate, (N,N-diethylcarbamoyl)methyl maleic acid,bis(N,N-diethylcarbamoyl)methyl maleate, dimethyl maleate, methylmaleate, and maleic acid; as well as any salts thereof.

In some embodiments, each of the one or more compounds of Formula (XIII)is present in an amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIII) is present in an amount of less than about0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XIII) ispresent in an amount of less than about 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIII) is present in an amount of less than about0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XIII) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (XIII)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIII) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XIII) ispresent in an amount of about 0.001% to 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIII) is present in an amount of about 0.001% to0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compound of Formula (XIII) ispresent in an amount of about 0.001% to 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In a fifteenth aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) one or more maleate compounds ofFormula (XV):

and salts of any of the foregoing, wherein:

R⁴¹ is (N,N-diethylcarbamoyl)methyl; and

R⁴² is chosen from hydrogen, ethyl, and (N,N-diethylcarbamoyl)methyl.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (XV) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XV) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XV) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of less than about 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of less thanabout 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of less than about 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of less thanabout 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of less than about 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of less thanabout 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of less than about 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XV) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of about 0.001%to 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of about 0.001% to 1.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of about 0.001%to 1.0% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XV) are present in a combined total amount of about 0.001%to 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XV) are present in acombined total amount of about 0.001% to 0.1% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XV) areselected from the group consisting of(2E)-3-(((N,N-diethylcarbamoyl)methyl)oxycarbonyl)prop-2-enoic acid;(N,N-diethylcarbamoyl)methyl ethyl (2E)but-2-ene-1,4-dioate; andbis(N,N-diethylcarbamoyl)methyl(2E)but-2-ene-1,4-dioate; as well as anysalts thereof.

In some embodiments, each of the one or more compounds of Formula (XV)is present in an amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XV) is present in an amount of less than about0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XV) ispresent in an amount of less than about 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XV) is present in an amount of less than about0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XV) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (XV)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XV) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XV) ispresent in an amount of about 0.001% to 0.15% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XV) is present in an amount of about 0.001% to0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compound of Formula (XV) is presentin an amount of about 0.001% to 0.05% by weight based on the totalweight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.

In another aspect, a pharmaceutical composition is provided whichcomprises (a) (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) N,N-diethyl-2-hydroxyacetamide:

and salts of any of the foregoing.

In some embodiments, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is incrystalline form. In some embodiments, the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, N,N-diethyl-2-hydroxyacetamide is present in atotal combined amount of less than 2 wt % based on the total weight ofthe (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, N,N-diethyl-2-hydroxyacetamide is present in atotal combined amount of less than 1 wt % based on the total weight ofthe (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of less than about 2% by weight based on the totalweight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofless than about 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in a combinedtotal amount of less than about 1.6% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofless than about 1.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in a combinedtotal amount of less than about 1.0% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofless than about 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in a combinedtotal amount of less than about 0.4% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofless than about 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of about 0.001% to 2% by weight based on the totalweight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofabout 0.001% to 1.8% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in a combinedtotal amount of about 0.001% to 1.6% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofabout 0.001% to 1.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in a combinedtotal amount of about 0.001% to 1.0% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofabout 0.001% to 0.6% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in a combinedtotal amount of about 0.001% to 0.4% by weight based on the total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments,N,N-diethyl-2-hydroxyacetamide is present in a combined total amount ofabout 0.001% to 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, N,N-diethyl-2-hydroxyacetamide is present in anamount of less than about 0.2% by weight based on the total weight ofthe (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in an amountof less than about 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in an amount ofless than about 0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in an amount ofless than about 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in an amount ofless than about 0.05% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In some embodiments, N,N-diethyl-2-hydroxyacetamide is present in anamount of about 0.001% to 0.3% by weight based on the total weight ofthe (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Insome embodiments, N,N-diethyl-2-hydroxyacetamide is present in an amountof about 0.001% to 0.2% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in an amount ofabout 0.001% to 0.15% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in an amount ofabout 0.001% to 0.1% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. In someembodiments, N,N-diethyl-2-hydroxyacetamide is present in an amount ofabout 0.001% to 0.05% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate

Regulatory authorities worldwide require the amounts of impurities to bemaintained at the lowest possible levels in pharmaceutical compositionsand formulations. Hence there exists a need for stabilized compositionsof methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

If exposed to sufficient amounts of light or if sufficiently exposed toan oxidant, methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate isprone to a number of reactions such as oxidative stress andphotodegradation, which gives rise to impurities. Two of severalimpurities which can be generated are tetramethylcyclobutane-1,2,3,4-tetracarboxylate formed by photodegradation andtransesterification of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and dimethyl oxirane-2,3-dicarboxylate formedby oxidation and transesterification of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In a seventh aspect, a dosage form is provided which comprises (a) atherapeutically effective amount of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate; (b) one or more cyclobutane compounds ofFormula (VII):

and salts of any of the foregoing, wherein:

each of R¹⁹ through R²² is independently chosen from hydrogen, methyl,and (N,N-diethylcarbamoyl)methyl; and

wherein the one or more compounds of Formula (VII) are present in atotal combined amount of less than 2% by weight based on total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and (c) apharmaceutically acceptable vehicle.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (VII) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VII) are present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VII) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of less thanabout 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VII) are present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VII) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VII) are present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VII) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VII) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VII) are present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VII) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (I) are present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VII) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VII) are present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VII) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VII) arepresent in a total combined amount of less than about 2% by weight basedon total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VII) are present in a total combined amount of less thanabout 1% by weight based on total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (VII) include1,2-bis(methoxycarbonyl)-3,4-bis(4-morpholin-4-ylbutoxycarbonyl)cyclobutane;1,3-bis(methoycarbonyl)-2,4-bis(4-morpholin-4-ylbutoxycarbonyl)cyclobutane;1-methoxycarbonyl-2-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-3,4-dicarboxylicacid; 1,2-bis(methoxycarbonyl)cyclobutane-2,3-dicarboxylic acid;1,3-bis(methoxycarbonyl)cyclobutane-2,4-dicarboxylic acid;1,2-bis-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-3,4-dicarboylicacid; 1,3-bis-(4-morpholin-4-ylbutyl)cyclobutane-2,4-dicarboylic acid;cyclobutane-1,2,3,4-tetracarboxylic acid;1,2-bis(methoxycarbonyl)-3-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-4-carboxylicacid;1,2-bis-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-3,4-dicarboxylicacid;1,2-bis(4-morpholin-4-ylbutoxycarbonyl)-3-(methoxycarbonyl)cyclobutane-4-carboxylicacid;1,2-bis(methoxycarbonyl)-3-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-4-carboxylicacid; 1-methoxycarbonyl-2,3-bis-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-4-carboxylic acid;1-(methoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid; and1-(4-morpholin-4-ylbutoxycarbonyl)cyclobutane-2,3,4-tricarboxylic acid;as well as salts of any of the foregoing.

In some embodiments, the isomers of compounds of Formula (VII) include,1R,2R,3R,4R-, 1S,2S,3S,4S-, 1R,2R,3S,4S-, or 1R,2S,3R,4S-isomers.

In some embodiments, the compounds of Formula (VII) include1R,2R,3S,4S-isomers.

In some embodiments, each of the one or more compounds of Formula (VII)is present in an amount of less than about 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VII) is present in an amount of less than about0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (VII) is present in anamount of less than about 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VII) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VII) is present in an amount of less than about0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (VII)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VII) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (VII) is present in anamount of about 0.001% to 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VII) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VII) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In order to maintain a low content of photodegradant compounds ofFormula (I) in a methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical composition or dosageform, the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate activepharmaceutical ingredient as well as the dosage form should both bemanufactured with minimal exposure to visible and/or UV light. Thus,methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate powder should beexposed to visible and UV light levels below these limits in order tomaintain the levels of photodegradant compounds of Formula (I) withinacceptable ranges.

In order to reduce the impact of light, including natural light,ultra-violet light and near-UV light, on the stability of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate in a methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate-containing dosage form, abarrier layer or coating can be applied to the dosage form. For oraldosage forms, examples include a coating on a methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate-containing tablet or anopaque capsule containing methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate particles or pellets.

In some embodiments, the tablet or capsule coating is opaque and has athickness of at least 10 μm. In some embodiments, the coating has athickness of at least 300 μm. The coating may comprise a filler and/or apolymer. The coating may comprise an iron oxide colorant and otherexcipients. Alternatively, the coating may comprise a colorant (e.g.,FD&C Yellow #6, Sunset Yellow, or FD&C Red #40 Allura Red) and otherknown coating excipients. Alternatively, the coating may comprisetitanium dioxide, silicon dioxide or zinc dioxide and other knowncoating excipients.

The use of opaque plastic (e.g., high density polyethylene) pillbottles, e.g., with child-resistant screw caps, is one option to limitthe amount of light exposure to a methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing dosage form. Blister packs, a termused for several types of pre-formed plastic pharmaceutical packaging,is another option. The primary component of a blister pack is a cavityor pocket made from a formable web, usually a thermoformed plastic. Thisusually has a backing of paperboard or a lidding seal of aluminum foilor plastic. The plastics can be made opaque, and/or with an anti-UVlight coating, to limit the amount of light exposure to the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate dosage form.

In an eighth aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) one or more succinate compounds of Formula (VIII):

and salts of any of the foregoing, wherein:

each of R²³ and R²⁵ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl;

Y is chosen from O, S, NH and NR²⁶;

R²⁴ is chosen from hydrogen, lower alkyl, and aryl; and

R²⁶ is chosen from lower alkyl.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, each of R²⁴ and R²⁶ is unsubstituted alkyl. In someembodiments, each of R²⁴ and R²⁶ is independently alkyl, substitutedwith hydroxy.

In some embodiments, the one or more compounds of Formula (VIII) arepresent in a total combined amount of less than 3 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VIII) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VIII) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VIII) arepresent in a combined total amount of less than about 3% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of less thanabout 2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of less than about 1.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VIII) are present ina combined total amount of less than about 1.6% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of less thanabout 1.4% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds) of Formula (VIII) are present in a combined totalamount of less than about 1.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VIII) are present ina combined total amount of less than about 1.0% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of less thanabout 0.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of less than about 0.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VIII) are present ina combined total amount of less than about 0.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of less thanabout 0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of less than about 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (VIII) arepresent in a combined total amount of about 0.001% to 3% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of about 0.001%to 2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of about 0.001% to 1.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VIII) are present ina combined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of about 0.001%to 1.4% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of about 0.001% to 1.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VIII) are present ina combined total amount of about 0.001% to 1.0% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of about 0.001%to 0.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of about 0.001% to 0.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (VIII) are present ina combined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (VIII) are present in a combined total amount of about 0.001%to 0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (VIII) are present in a combined totalamount of about 0.001% to 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (VIII) include the following:methyl-(4-morpholin-4-ylbutyl)-hydroxysuccinate;(4-morpholin-4-ylbutyl)-hydroxysuccinic mono-acid; methylhydroxysuccinicmono-acid; hydroxysuccinic acid;methyl-(4-morpholin-4-ylbutyl)-mercaptosuccinate;(4-morpholin-4-ylbutyl)-mercaptosuccinic mono-acid;methyl-mercaptosuccinic mono-acid; mercaptosuccinic acid;methyl-(4-morpholin-4-ylbutyl)-aminosuccinate;(4-morpholin-4-ylbutyl)-aminosuccinic mono-acid; methylaminosuccinicmono-acid; and aminosuccinic acid; as well as salts of any of theforegoing.

In some embodiments, each of the one or more compounds of Formula (VIII)is present in an amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VIII) is present in an amount of less than about0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (VIII) is present in anamount of less than about 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VIII) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (VIII)is present in an amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (VIII) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (VIII) is present in anamount of about 0.001% to 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (VIII) ispresent in an amount of about 0.001% to 0.05% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no alkanols or alcohols,thioalkanols or alkyl mercaptans, alkylamines, dialkylamines or anycompound capable of acting as a nucleophile for addition to the doublebond of methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. Forexample, use of alcohols in a pharmaceutical composition can form the2-alkoxy compound (Formula VIII, —Y—R²⁴ is —O-alkyl) impurities into theformulation. Similarly, use of thioalcohols or mercaptans in apharmaceutical composition can form the 2-thioalkoxy compound (FormulaVIII, —Y—R²⁴ is —S-alkyl) impurities into the formulation. Furthermore,use of primary amines in a pharmaceutical composition can form the2-alkylamino compound (Formula VIII, —Y—R²⁴ is —NH-alkyl) impuritiesinto the formulation. Moreover, use of secondary amines in apharmaceutical composition can firm the 2-dialkylamino compound (FormulaVIII, —Y—R²⁴ is —N(alkyl)₂) impurities into the formulation.

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of any alcohols,mercaptans, alkylamines, or dialkylamines. In some embodiments, thepharmaceutical compositions and dosage forms disclosed herein aresubstantially free of methanol, ethanol, methyl mercaptan, ethylamine,propylamine, butylamine, aspartame, diethanolamine, meglumine,monoethanolamine, or triethanolamine.

In a ninth aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) an oxirane compound of Formula (IX):

and salts of any of the foregoing, wherein:

each of R²⁷ and R²⁸ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl; and

wherein the one or more compounds of Formula (IX) are present in thedosage form in a combined total amount of less than 3% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In another aspect, a dosage form is provided which comprises (a) methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and (b) an oxiranecompound of Formula (IX):

and salts of any of the foregoing, wherein:

each of R²⁷ and R²⁸ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl; and

wherein the one or more compounds of Formula (IX) are present in thedosage form in a combined total amount of less than 3% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments of the pharmaceutical compositions and/or dosageforms, the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate issolid. In some embodiments of the pharmaceutical compositions and/ordosage forms, the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioateis crystalline. In some embodiments of the pharmaceutical compositionsand/or dosage forms, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is amorphous.

In some embodiments, the one or more compounds of Formula (IX) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (IX) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (IX) arepresent in a combined total amount of less than about 3% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of less thanabout 2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of less than about 1.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IX) are present in acombined total amount of less than about 1.6% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of less thanabout 1.4% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds) of Formula (IX) are present in a combined totalamount of less than about 1.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IX) are present in acombined total amount of less than about 1.0% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of less thanabout 0.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of less than about 0.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IX) are present in acombined total amount of less than about 0.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of less thanabout 0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of less than about 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (IX) arepresent in a combined total amount of about 0.001% to 3% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of about 0.001%to 2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of about 0.001% to 1.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IX) are present in acombined total amount of about 0.001% to 1.6% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of about 0.001%to 1.4% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of about 0.001% to 1.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IX) are present in acombined total amount of about 0.001% to 1.0% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of about 0.001%to 0.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of about 0.001% to 0.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (IX) are present in acombined total amount of about 0.001% to 0.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (IX) are present in a combined total amount of about 0.001%to 0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (IX) are present in a combined totalamount of about 0.001% to 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments of the pharmaceutical compositions and/or dosageforms, the one or more compounds of Formula (IX) include the following:dimethyl oxirane-2,3-dicarboxylate (compound (2)), in which both R²⁷ andR²⁸ are methyl; 3-(methoxycarbonyl)oxirane-2-carboxylic acid, in whichR²⁷ is methyl and R²⁸ is hydrogen; oxirane-2,3-dicarboxylic acid, inwhich both R²⁷ and R²⁸ are hydrogen; and salts of any of the foregoing.

In some embodiments, each of the one or more compounds of Formula (IX)is present in an amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (IX) is present in an amount of less than about0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (IX) is present in anamount of less than about 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (IX) ispresent in an amount of less than about 0.05% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (IX)is present in an amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (IX) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (IX) is present in anamount of about 0.001% to 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (IX) ispresent in an amount of about 0.001% to 0.05% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments of the pharmaceutical compositions and/or dosageforms, the one or more compounds of Formula (IX) comprise dimethyloxirane-2,3-dicarboxylate, and salts of any of the foregoing. In someembodiments of the pharmaceutical compositions and/or dosage forms, theone or more compounds of Formula (IX) comprise dimethyloxirane-2,3-dicarboxylate. In other embodiments, the one or morecompounds of Formula (IX) are selected from the group consisting ofcis-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate;cis-(methoxycarbonyl)oxirane carboxylic mono-acid;cis-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylic mono-acid;cis-oxirane 2,3-dicarboxylic acid;trans-(N,N-diethylcarbamoyl)methyl-methyl oxirane dicarboxylate;trans-(methoxycarbonyl)oxirane carboxylic mono-acid;trans-(N,N-diethylcarbamoyl)methoxycarbonyl oxirane carboxylicmono-acid; and trans-oxirane 2,3-dicarboxylic acid; as well as salts ofany of the foregoing.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no polyvinylpyrrolidone(PVP) or polyethylene glycol (PEG). Use of polyvinylpyrrolidone (PVP) ina pharmaceutical composition can introduce peroxide impurities into theformulation since the PVP polymerization process involves the use ofpolymerization initiators such as peroxides, ozone, and hydrogenperoxides. Upon heat or light exposure, even trace amounts of peroxidescan decompose into free radicals, which can powerfully catalyzephotochemical reactions. Light-induced decomposition of polyoxyethylenechains of polyethylene glycols (PEG) or polysorbate surfactants can alsoresult in the formation of hydrogen peroxides and/or peroxide-freeradicals, which can promote degradation of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of anypolyvinylpyrrolidone, polyethylene glycol and/or polysorbate surfactant.In some embodiments, the pharmaceutical compositions and dosage formsdisclosed herein contain no polyvinylpyrrolidone, polyethylene glycoland/or polysorbate surfactant.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein may comprise an antioxidant. Suitableantioxidants include methyl paraben and propyl paraben and their salts(such as sodium, potassium), vitamin E, vitamin E TPGS, propyl gallate,sulfites, ascorbic acid, sodium benzoate, citric acid, cyclodextrins,peroxide scavengers, benzoic acid, ethylenediaminetetraacetic acid(EDTA) and salts thereof, chain terminators (e.g., thiols and phenols),butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and thelike, and combinations of any of the foregoing. In some embodiments,antioxidants such as butylated hydroxytoluene (BHT) and butylatedhydroxyanisole (BHA) can be used. In some embodiments, the antioxidantmay be present in an amount of about from 0.01 to 5.0%, and in someembodiments about from 0.5 to 2.0% by weight of the total pharmaceuticalcomposition.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein may comprise an antioxidant. Suitable freeradical scavengers include tocopherol, naringenin and the like, andmixtures thereof.

In another aspect, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms comprise one or more vehicles or other excipients that arelow in oxidizing agents such as hydrogen peroxide, formaldehydes andformic acid and low in metallic impurities such as iron ions (e.g.,Fe⁺²) that have the capability to oxidize methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In a tenth aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) one or more succinate compounds of Formula (X):

and salts of any of the foregoing, wherein:

each of R²⁹ and R³⁰ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (X) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (X) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (X) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of less than about1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (X) are present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (X) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of less than about1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (X) are present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (X) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of less than about0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (X) are present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (X) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of less than about0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (X) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of about 0.001% to1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (X) are present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (X) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of about 0.001% to1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (X) are present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (X) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of about 0.001% to0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (X) are present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (X) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (X) are present in a combined total amount of about 0.001% to0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (X) include the following: dimethyl succinate inwhich both R²⁹ and R³⁰ are methyl; 4-methoxy-4-oxobutanoic acid in whichR²⁹ is methyl and R³⁰ is hydrogen; succinic acid in which both R²⁹ andR³⁰ are hydrogen; and salts of any of the foregoing. In someembodiments, the one or more compounds of Formula (X) are selected fromthe group consisting of methyl-(4-morpholin-4-ylbutyl)-succinate;(4-morpholin-4-ylbutyl)-succinic mono-acid; methylsuccinic mono-acid;and succinic acid; as well as any salts of any of the foregoing.

In some embodiments, each of the one or more compounds of Formula (X) ispresent in an amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (X) is present in an amount of less than about 0.2%by weight based on the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (X) is present in an amount of less than about0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (X) is present in an amountof less than about 0.1% by weight based on the total weight of themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (X) is presentin an amount of less than about 0.05% by weight based on the totalweight of the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (X) ispresent in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (X) is present in an amount of about 0.001% to 0.2%by weight based on the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (X) is present in an amount of about 0.001% to0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (X) is present in an amountof about 0.001% to 0.1% by weight based on the total weight of themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compound of Formula (X) is presentin an amount of about 0.001% to 0.05% by weight based on the totalweight of the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no compound(s) capableof forming (N,N-diethylcarbamoyl) methyl, hydrogen or hydrogen radicalswhich will, in turn, facilitate the reduction of the double bond ofmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of any compoundscontaining hydrazino group.

In an eleventh aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) one or more succinate compounds of Formula (XI):

and salts of any of the foregoing wherein:

each of R³¹ and R³² is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (XI) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XI) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XI) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XI) are present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XI) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of less thanabout 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XI) are present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XI) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XI) are present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XI) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XI) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XI) are present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XI) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XI) are present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XI) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XI) are present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XI) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XI) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (XI) include the following: 2,3-dihydroxysuccinicacid dimethyl ester, in which both R¹³ and R¹⁴ are methyl;2,3-dihydroxysuccinic acid monomethyl ester, in which R¹³ is methyl andR¹⁴ is hydrogen; 2,3-dihydroxysuccinic acid, in which both R¹³ and R¹⁴are hydrogen; and salts of any of the foregoing. In some embodiments,the one or more compound of Formula (XI) are selected from the groupconsisting of methyl-(4-morpholin-4-ylbutyl)-2,3-dihydroxysuccinate;(4-morpholin-4-ylbutyl)-2,3-dihydroxysuccinic mono-acid;methyl-2,3-dihydroxysuccinic mono-acid; and 2,3-dihydroxysuccinic acid(tartaric acid); as well as any salts thereof.

In some embodiments, each of the one or more compounds of Formula (XI)is present in an amount of less than about 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XI) is present in an amount of less than about0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XI) is present in anamount of less than about 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XI) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XI) is present in an amount of less than about0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (XI)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XI) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XI) is present in anamount of about 0.001% to 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XI) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XI) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no compound(s) capableof isomerizing the double bond of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain antioxidants and/or free radicalscavengers.

In a twelfth aspect, a dosage form is provided which comprises (a)methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and (b) one ormore compounds of Formula (XII):

and salts of any of the foregoing, wherein:

Q is —O—, —S—, —NH—, —N(R³⁵)—, or C(R³⁶)₂;

each of R³³ and R³⁴ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbomoyl)methyl;

R³⁵ is (N,N-diethylcarbamoyl)methyl or alkyl; and

each R³⁶ is independently hydrogen or alkyl; and

(c) a pharmaceutically acceptable vehicle.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (XII) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XII) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XII) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XII) are present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XII) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of less thanabout 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XII) are present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XII) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XII) are present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XII) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XII) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XII) are present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XII) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XII) are present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XII) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XII) are present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XII) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XII) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Compounds of Formula (XII) include the following compounds, wherein:

Q is —O—, and each R³³ and R³⁴ is methyl;

Q is —O—, and each R³³ and R³⁴ is H;

Q is —O—, and each R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —O—, R³³ is H, and R³⁴ is methyl;

Q is —O—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —O—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —S—, and each of R³³ and R³⁴ is methyl;

Q is —S—, and each of R³³ and R³⁴ is H;

Q is —S—, and each of R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —S—, R³³ is H, and R³⁴ is methyl;

Q is —S—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —S—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NH—, and each of R³³ and R³⁴ is methyl;

Q is —NH—, and each of R³³ and R³⁴ is H;

Q is —NH—, and each of R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NH—, R³³ is H, and R³⁴ is methyl;

Q is —NH—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NH—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NMe—, and each of R³³ and R³⁴ is methyl;

Q is —NMe—, and each of R³³ and R³⁴ is H;

Q is —NMe—, and each of R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NMe—, R³³ is H, and R³⁴ is methyl;

Q is —NMe—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —NMe—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —CH₂—, and each R³³ and R³⁴ is methyl;

Q is —CH₂—, and each R³³ and R³⁴ is H;

Q is —CH₂—, and each R³³ and R³⁴ is 4-morpholin-4-ylbutyl;

Q is —CH₂—, R³³ is H, and R³⁴ is methyl;

Q is —CH₂—, R³³ is H, and R³⁴ is 4-morpholin-4-ylbutyl; and

Q is —CH₂—, R³³ is methyl, and R³⁴ is 4-morpholin-4-ylbutyl;

isomers of any of the foregoing compounds and salts of any of theforegoing compounds.

In some embodiments, each of the one or more compounds of Formula (XII)is present in an amount of less than about 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XII) is present in an amount of less than about0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XII) is present in anamount of less than about 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XII) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XII) is present in an amount of less than about0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (XII)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XII) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XII) is present in anamount of about 0.001% to 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XII) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XII) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In another aspect, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate-containing pharmaceutical compositions anddosage forms disclosed herein contain little or no compound(s) capableof reacting with methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioateto form Diels-Alder products.

For example, methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate,which can act as dienophile, will react with cyclopentadiene, furan,thiofurans, or pyrroles, to form Diels-Alder cyclization products asshown below, where Q, R³³ and R³⁴ are as defined herein:

Thus in some embodiments, the pharmaceutical compositions and dosageforms disclosed herein are substantially free of any compoundscontaining furan, thiophene, and pyrrole moieties.

In a fourteenth aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) one or more maleate compounds of Formula (XIV):

and salts of any of the foregoing, wherein:

each of R³⁹ and R⁴⁹ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (XIV) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIV) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIV) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XIV) are present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIV) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of less thanabout 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XIV) are present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIV) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XIV) are present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIV) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIV) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XIV) are present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIV) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XIV) are present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIV) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XIV) are present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XIV) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XIV) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XIV) areselected from the group consisting of 4-morpholin-4-ylbutyl methylmaleate, 4-morpholin-4-ylbutyl maleic acid, bis(4-morpholin-4-ylbutyl)maleate, dimethyl maleate, methyl maleate, and maleic acid; as well asany salts of any of the foregoing.

In some embodiments, each of the one or more compounds of Formula (XIV)is present in an amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIV) is present in an mount of less than about0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XIV) is present in anamount of less than about 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XIV) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIV) is present in an amount of less than about0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (XIV)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XIV) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XIV) is present in anamount of about 0.001% to 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XIV) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompound of Formula (XIV) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In a sixteenth aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) one or more maleate compounds of Formula (XVI):

salts of any of the foregoing, wherein:

R⁴³ is 4-morpholin-4-ylbutyl; and

R⁴⁴ is chosen from hydrogen, ethyl, and 4-morpholin-4-ylbutyl.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, the one or more compounds of Formula (XVI) arepresent in a total combined amount of less than 2 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XVI) arepresent in a total combined amount of less than 1 wt % based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XVI) arepresent in a combined total amount of less than about 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of less thanabout 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XVI) are present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XVI) are present in acombined total amount of less than about 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of less thanabout 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XVI) are present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XVI) are present in acombined total amount of less than about 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of less thanabout 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XVI) are present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XVI) are present in acombined total amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of less thanabout 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XVI) arepresent in a combined total amount of about 0.001% to 2% by weight basedon the total weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of about 0.001%to 1.8% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XVI) are present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XVI) are present in acombined total amount of about 0.001% to 1.4% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of about 0.001%to 1.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XVI) are present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XVI) are present in acombined total amount of about 0.001% to 0.8% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of about 0.001%to 0.6% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments, theone or more compounds of Formula (XVI) are present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, the one or more compounds of Formula (XVI) are present in acombined total amount of about 0.001% to 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the one or more compoundsof Formula (XVI) are present in a combined total amount of about 0.001%to 0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, the one or more compounds of Formula (XVI) areselected from the group consisting of(2E)-3-((4-morpholin-4-ylbutyl)oxycarbonyl)prop-2-enoic acid; ethyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-diate; andbis-(4-morpholin-4-ylbutyl) (2E)but-2-ene-1,4-dioate; as well as anysalts of any of the foregoing.

In some embodiments, each of the one or more compounds of Formula (XVI)is present in an amount of less than about 0.2% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XVI) is present in an amount of less than about0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XVI) is present in anamount of less than about 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XVI) ispresent in an amount of less than about 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XVI) is present in an amount of less than about0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, each of the one or more compounds of Formula (XVI)is present in an amount of about 0.001% to 0.3% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompounds of Formula (XVI) is present in an amount of about 0.001% to0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,each of the one or more compounds of Formula (XVI) is present in anamount of about 0.001% to 0.15% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, each of the one or more compounds of Formula (XVI) ispresent in an amount of about 0.001% to 0.1% by weight based on thetotal weight of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, each of the one or morecompound of Formula (XVI) is present in an amount of about 0.001% to0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In another aspect, a pharmaceutical composition is provided whichcomprises (a) methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and(b) 4-morpholin-4-ylbutan-1-ol, and salts of any of the foregoing.

In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in solid form. In some embodiments, themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is in crystallineform. In some embodiments, the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate is in amorphous form.

In some embodiments, 4-morpholin-4-ylbutan-1-ol is present in a totalcombined amount of less than 2 wt % based on the total weight of themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, 4-morpholin-4-ylbutan-1-ol is present in a totalcombined amount of less than 1 wt % based on the total weight of themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, 4-morpholin-4-ylbutan-1-ol is present in a combinedtotal amount of less than about 2% by weight based on the total weightof the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 1.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 1.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 1.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 0.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 0.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 0.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of less than about 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, 4-morpholin-4-ylbutan-1-ol is present in a combinedtotal amount of about 0.001% to 2% by weight based on the total weightof the methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 1.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 1.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 1.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 1.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 1.0% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 0.8% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 0.6% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 0.4% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 0.2% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in a combined totalamount of about 0.001% to 0.1% by weight based on the total weight ofthe methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, 4-morpholin-4-ylbutan-1-ol is present in an amountof less than about 0.2% by weight based on the total weight of themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in an amount of lessthan about 0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,4-morpholin-4-ylbutan-1-ol is present in an amount of less than about0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,4-morpholin-4-ylbutan-1-ol is present in an amount of less than about0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,4-morpholin-4-ylbutan-1-ol is present in an amount of less than about0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In some embodiments, 4-morpholin-4-ylbutan-1-ol is present in an amountof about 0.001% to 0.3% by weight based on the total weight of themethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In someembodiments, 4-morpholin-4-ylbutan-1-ol is present in an amount of about0.001% to 0.2% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,4-morpholin-4-ylbutan-1-ol is present in an amount of about 0.001% to0.15% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,4-morpholin-4-ylbutan-1-ol is present in an amount of about 0.001% to0.1% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. In some embodiments,4-morpholin-4-ylbutan-1-ol is present in an amount of about 0.001% to0.05% by weight based on the total weight of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically effective amount of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate togetherwith a suitable amount of one or more pharmaceutically acceptablevehicles so as to provide a composition for proper administration to apatient. Suitable pharmaceutical vehicles are described in the art.

In certain embodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be incorporated into pharmaceuticalcompositions to be administered orally. Oral administration of suchpharmaceutical compositions may result in uptake of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate throughoutthe intestine and entry into the systemic circulation. Such oralcompositions may be prepared in a manner known in the pharmaceutical artand comprise (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and at least one pharmaceutically acceptablevehicle. Oral pharmaceutical compositions may include a therapeuticallyeffective amount of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and a suitable amount of a pharmaceuticallyacceptable vehicle, so as to provide an appropriate form foradministration to a patient.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may beincorporated into pharmaceutical compositions to be administered by anyother appropriate route of systemic administration includingintramuscular, intravenous and oral.

Pharmaceutical compositions comprising (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping, or lyophilizing processes.Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers, diluents,excipients, or auxiliaries, which facilitate processing of the compoundor crystalline forms thereof and one or more pharmaceutically acceptablevehicles into formulations that can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Pharmaceutical compositions provided by the present disclosure take theform of sustained-release formulations suitable for administration to apatient.

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. A unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioatecalculated to produce an intended therapeutic effect. A unit dosage formmay be for a single daily dose, for administration 2 times per day, orone of multiple daily doses, e.g., 3 or more times per day. Whenmultiple daily doses are used, a unit dosage form may be the same ordifferent for each dose. One or more dosage forms may comprise a dose,which may be administered to a patient at a single point in time orduring a time interval.

In certain embodiments, an oral dosage form provided by the presentdisclosure may be a controlled release dosage form. Controlled deliverytechnologies can improve the absorption of a drug in a particular regionor regions of the gastrointestinal tract. Controlled drug deliverysystems may be designed to deliver a drug in such a way that the druglevel is maintained within a therapeutically effective window andeffective and safe blood levels are maintained for a period as long asthe system continues to deliver the drug with a particular releaseprofile in the gastrointestinal tract. Controlled drug delivery mayproduce substantially constant blood levels of a drug over a period oftime as compared to fluctuations observed with immediate release dosageforms. For some applications, maintaining a constant blood and tissueconcentration throughout the course of therapy is the most desirablemode of treatment. Immediate release of drug may cause blood levels topeak above the level required to elicit a desired response, which maywaste the drug and may cause or exacerbate toxic side effects.Controlled drug delivery can result in optimum therapy, and not only canreduce the frequency of dosing, but may also reduce the severity of sideeffects. Examples of controlled release dosage forms include dissolutioncontrolled systems, diffusion controlled systems, ion exchange resins,osmotically controlled systems, erodible matrix systems, pH independentformulations, gastric retention systems, and the like.

An appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and/or thestability of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in the gastrointestinal tract, thepharmacokinetics of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and the intended therapeutic profile. Anappropriate controlled release oral dosage form may be selected for aparticular compound. For example, gastric retention oral dosage formsmay be appropriate for compounds absorbed primarily from the uppergastrointestinal tract, and sustained release oral dosage forms may beappropriate for compounds absorbed primarily from the lowergastrointestinal tract. Certain compounds are absorbed primarily fromthe small intestine. In general, compounds traverse the length of thesmall intestine in about 3 to 5 hours. For compounds that are not easilyabsorbed by the small intestine or that do not dissolve readily, thewindow for active agent absorption in the small intestine may be tooshort to provide a desired therapeutic effect.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may be practiced with dosage forms adapted to providesustained release of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate upon oral administration. Sustained releaseoral dosage forms may be used to release drugs over a prolonged timeperiod and are useful when it is desired that a drug or drug form bedelivered to the lower gastrointestinal tract, including the colon.Sustained release oral dosage forms include any oral dosage form thatmaintains therapeutic concentrations of a drug in a biological fluidsuch as the plasma, blood, cerebrospinal fluid, or in a tissue or organfor a prolonged time period. Sustained release oral dosage forms includediffusion-controlled systems such as reservoir devices and matrixdevices, dissolution-controlled systems, osmotic systems, anderosion-controlled systems. Sustained release oral dosage forms andmethods of preparing the same are well known in the art.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any enteric-coated sustained release oraldosage form for administering (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. In some embodiments, the enteric-coated oraldosage form is administered to a patient at a dosing frequency of threetimes per day. In some embodiments, the enteric-coated oral dosage formis administered to a patient at a dosing frequency of twice per day. Insome embodiments, the enteric-coated oral dosage form is administered toa patient at a dosing frequency of once per day.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any suitable dosage forms that achievethe above described in vitro release profiles. Such dosage forms may beany systemic dosage forms, including sustained release enteric-coatedoral dosage forms and sustained release enteric-coated ornon-enteric-coated oral dosage forms. Examples of suitable dosage formsare described herein. Those skilled in the formulation art can developany number of acceptable dosage forms given the dosage forms describedin the examples as a starting point.

An appropriate dose of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be determined according to any one ofseveral well-established protocols. For example, animal studies such asstudies using mice, rats, dogs, and/or monkeys may be used to determinean appropriate dose of a pharmaceutical compound. Results from animalstudies may be extrapolated to determine doses for use in other species,such as for example, humans.

In other embodiments, pharmaceutical compositions provided by thepresent disclosure may comprise a therapeutically effective amount ofmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate together with asuitable amount of one or more pharmaceutically acceptable vehicles soas to provide a composition for proper administration to a patient.Suitable pharmaceutical vehicles are described in the art.

In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be incorporated into pharmaceuticalcompositions to be administered orally. Oral administration of suchpharmaceutical compositions may result in uptake of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate throughout the intestineand entry into the systemic circulation. Such oral compositions may beprepared in a manner known in the pharmaceutical art and comprise methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate and at least onepharmaceutically acceptable vehicle. Oral pharmaceutical compositionsmay include a therapeutically effective amount of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate and a suitable amount ofa pharmaceutically acceptable vehicle, so as to provide an appropriateform for administration to a patient.

Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may beincorporated into pharmaceutical compositions to be administered by anyother appropriate route of systemic administration includingintramuscular, intravenous and oral.

Pharmaceutical compositions comprising methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore physiologically acceptable carriers, diluents, excipients, orauxiliaries, which facilitate processing of the compound or crystallineforms thereof and one or more pharmaceutically acceptable vehicles intoformulations that can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions provided by the present disclosure take the form ofsustained-release formulations suitable for administration to a patient.

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. A unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate calculated toproduce an intended therapeutic effect. A unit dosage form may be for asingle daily dose, for administration 2 times per day, or one ofmultiple daily doses, e.g., 3 or more times per day. When multiple dailydoses are used, a unit dosage form may be the same or different for eachdose. One or more dosage forms may comprise a dose, which may beadministered to a patient at a single point in time or during a timeinterval.

In certain embodiments, an oral dosage form provided by the presentdisclosure may be a controlled release dosage form. Controlled deliverytechnologies can improve the absorption of a drug in a particular regionor regions of the gastrointestinal tract. Controlled drug deliverysystems may be designed to deliver a drug in such a way that the druglevel is maintained within a therapeutically effective window andeffective and safe blood levels are maintained for a period as long asthe system continues to deliver the drug with a particular releaseprofile in the gastrointestinal tract. Controlled drug delivery mayproduce substantially constant blood levels of a drug over a period oftime as compared to fluctuations observed with immediate release dosageforms. For some applications, maintaining a constant blood and tissueconcentration throughout the course of therapy is the most desirablemode of treatment. Immediate release of drug may cause blood levels topeak above the level required to elicit a desired response, which maywaste the drug and may cause or exacerbate toxic side effects.Controlled drug delivery can result in optimum therapy, and not only canreduce the frequency of dosing, but may also reduce the severity of sideeffects. Examples of controlled release dosage forms include dissolutioncontrolled systems, diffusion controlled systems, ion exchange resins,osmotically controlled systems, erodible matrix systems, pH independentformulations, gastric retention systems, and the like.

An appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate and/or the stability ofmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate in thegastrointestinal tract, the pharmacokinetics of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate and the intendedtherapeutic profile. An appropriate controlled release oral dosage formmay be selected for a particular compound. For example, gastricretention oral dosage forms may be appropriate for compounds absorbedprimarily from the upper gastrointestinal tract, and sustained releaseoral dosage forms may be appropriate for compounds absorbed primarilyfrom the lower gastrointestinal tract. Certain compounds are absorbedprimarily from the small intestine. In general, compounds traverse thelength of the small intestine in about 3 to 5 hours. For compounds thatare not easily absorbed by the small intestine or that do not dissolvereadily, the window for active agent absorption in the small intestinemay be too short to provide a desired therapeutic effect.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may be practiced with dosage forms adapted to providesustained release of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate upon oral administration. Sustained releaseoral dosage forms may be used to release drugs over a prolonged timeperiod and are useful when it is desired that a drug or drug form bedelivered to the lower gastrointestinal tract, including the colon.Sustained release oral dosage forms include any oral dosage form thatmaintains therapeutic concentrations of a drug in a biological fluidsuch as the plasma, blood, cerebrospinal fluid, or in a tissue or organfor a prolonged time period. Sustained release oral dosage forms includediffusion-controlled systems such as reservoir devices and matrixdevices, dissolution-controlled systems, osmotic systems, anderosion-controlled systems. Sustained release oral dosage forms andmethods of preparing the same are well known in the art.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any enteric-coated sustained release oraldosage form for administering methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. In some embodiments, the enteric-coated oraldosage form is administered to a patient at a dosing frequency of threetimes per day. In some embodiments, the enteric-coated oral dosage formis administered to a patient at a dosing frequency of twice per day. Insome embodiments, the enteric-coated oral dosage form is administered toa patient at a dosing frequency of once per day.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any suitable dosage forms that achievethe above described in vitro release profiles. Such dosage forms may beany systemic dosage forms, including sustained release enteric-coatedoral dosage forms and sustained release enteric-coated ornon-enteric-coated oral dosage forms. Examples of suitable dosage formsare described herein. Those skilled in the formulation art can developany number of acceptable dosage forms given the dosage forms describedin the examples as a starting point.

An appropriate dose of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be determined according to any one ofseveral well-established protocols. For example, animal studies such asstudies using mice, rats, dogs, and/or monkeys may be used to determinean appropriate dose of a pharmaceutical compound. Results from animalstudies may be extrapolated to determine doses for use in other species,such as for example, humans.

Uses

The methods and compositions disclosed herein can be used to treatpatients suffering from diseases, disorders, conditions, and symptomsfor which (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateand/or other fumaric acid esters are known to provide, or are laterfound to provide, therapeutic benefit. (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate can be used to treat a disease chosenfrom adrenal leukodystrophy, AGE-induced genome damage, AlexanderDisease, Alper's Disease, Alzheimer's disease, amyotrophic lateralsclerosis, angina pectoris, arthritis, asthma, balo concentricsclerosis, Canavan disease, cardiac insufficiency including leftventricular insufficiency, central nervous system vasculitis,Charcott-Marie-Tooth Disease, childhood ataxia with central nervoussystem hypomyelination, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, Crohn's disease, diabeticretinopathy, graft versus host disease, hepatitis C viral infection,herpes simplex viral infection, human immunodeficiency viral infection,Huntington's disease, irritable bowel disorder, ischemia, KrabbeDisease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis and Zellweger's syndrome.

Methods of treating a disease in a patient provided by the presentdisclosure comprise administering to a patient in need of such treatmenta therapeutically effective amount of (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate. These methods and pharmaceuticalcompositions provide therapeutic or prophylactic plasma and/or bloodconcentrations of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate following administration to a patient.(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may beadministered in an amount and using a dosing schedule as appropriate fortreatment of a particular disease. Daily doses of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may rangefrom about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about50 mg/kg, from about 1 mg/kg to about 50 mg/kg, and in certainembodiments, from about 5 mg/kg to about 25 mg/kg. In certainembodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be administered at a dose over time fromabout 1 mg to about 5 g per day, from about 10 mg to about 4 g per day,in certain embodiments from about 20 mg to about 2 g per day, in certainembodiments from about 100 mg to about 1 g per day, in certainembodiments from about 200 mg to about 800 mg per day, in certainembodiments from about 300 mg to about 600 mg per day, and in certainembodiments from about 400 mg to about 500 mg per day. An appropriatedose of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate maybe determined based on several factors, including, for example, the bodyweight and/or condition of the patient being treated, the severity ofthe disease being treated, the incidence and/or severity of sideeffects, the manner of administration, and the judgment of theprescribing physician. Appropriate dose ranges may be determined bymethods known to those skilled in the art.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may beassayed in vitro and in vivo for the desired therapeutic or prophylacticactivity prior to use in humans. In vivo assays, for example usingappropriate animal models, may also be used to determine whetheradministration of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is therapeutically effective.

In certain embodiments, a therapeutically effective dose of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may providetherapeutic benefit without causing substantial toxicity includingadverse side effects. Toxicity of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and/or metabolites thereof may be determined asdescribed herein and/or by using standard pharmaceutical procedures andmay be ascertained by those skilled in the art. The dose ratio betweentoxic and therapeutic effect is the therapeutic index. A dose of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may bewithin a range capable of establishing and maintaining a therapeuticallyeffective circulating plasma and/or blood concentration of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate thatexhibits little or no toxicity.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateadministration may be used to treat a disease chosen from adrenalleukodystrophy, AGE-induced genome damage, Alexander Disease, Alper'sDisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcott-Marie-Tooth Disease, childhoodataxia with central nervous system hypomyelination, chronic idiopathicperipheral neuropathy, chronic obstructive pulmonary disease, Crohn'sdisease, diabetic retinopathy, graft versus host disease, hepatitis Cviral infection, herpes simplex viral infection, human immunodeficiencyviral infection, Huntington's disease, irritable bowel disorder,ischemia, Krabbe Disease, lichen planus, macular degeneration,mitochondrial encephalomyopathy, monomelic amyotrophy, multiplesclerosis, myocardial infarction, neurodegeneration with brain ironaccumulation, neuromyelitis optica, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, and Zellweger's syndrome. The underlying etiology ofany of the foregoing diseases being treated may have a multiplicity oforigins. Further, in certain embodiments, a therapeutically effectiveamount of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioatemay be administered to a patient, such as a human, as a preventativemeasure against the foregoing diseases and disorders. Thus, atherapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be administered as a preventative measureto a patient having a predisposition for and/or history of adrenalleukodystrophy, AGE-induced genome damage, Alexander Disease, Alper'sDisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcott-Marie-Tooth Disease, childhoodataxia with central nervous system hypomyelination, chronic idiopathicperipheral neuropathy, chronic obstructive pulmonary disease, Crohn'sdisease, diabetic retinopathy, graft versus host disease, hepatitis Cviral infection, herpes simplex viral infection, human immunodeficiencyviral infection, Huntington's disease, irritable bowel disorder,ischemia, Krabbe Disease, lichen planus, macular degeneration,mitochondrial encephalomyopathy, monomelic amyotrophy, multiplesclerosis, myocardial infarction, neurodegeneration with brain ironaccumulation, neuromyelitis optica, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, and/or Zellweger's syndrome.

In other embodiments, the methods and compositions disclosed herein canbe used to treat patients suffering from diseases, disorders,conditions, and symptoms for which methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and/or other fumaric acid esters are known toprovide, or are later found to provide, therapeutic benefit. Methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate can be used to treat adisease chosen from adrenal leukodystrophy, AGE-induced genome damage,Alexander Disease, Alper's Disease, Alzheimer's disease, amyotrophiclateral sclerosis, angina pectoris, arthritis, asthma, balo concentricsclerosis, Canavan disease, cardiac insufficiency including leftventricular insufficiency, central nervous system vasculitis,Charcott-Marie-Tooth Disease, childhood ataxia with central nervoussystem hypomyelination, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, Crohn's disease, diabeticretinopathy, graft versus host disease, hepatitis C viral infection,herpes simplex viral infection, human immunodeficiency viral infection,Huntington's disease, irritable bowel disorder, ischemia, KrabbeDisease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, and Zellweger's syndrome.

Methods of treating a disease in a patient provided by the presentdisclosure comprise administering to a patient in need of such treatmenta therapeutically effective amount of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. These methods and pharmaceutical compositionsprovide therapeutic or prophylactic plasma and/or blood concentrationsof methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate followingadministration to a patient. Methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be administered in an amount and using adosing schedule as appropriate for treatment of a particular disease.Daily doses of methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate mayrange from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg toabout 50 mg/kg, from about 1 mg/kg to about 50 mg/kg, and in certainembodiments, from about 5 mg/kg to about 25 mg/kg. In certainembodiments, methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate maybe administered at a dose over time from about 1 mg to about 5 g perday, from about 10 mg to about 4 g per day, in certain embodiments fromabout 20 mg to about 2 g per day, in certain embodiments from about 100mg to about 1 g per day, in certain embodiments from about 200 mg toabout 800 mg per day, in certain embodiments from about 300 mg to about600 mg per day, and in certain embodiments from about 400 mg to about500 mg per day. An appropriate dose of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be determined based on several factors,including, for example, the body weight and/or condition of the patientbeing treated, the severity of the disease being treated, the incidenceand/or severity of side effects, the manner of administration, and thejudgment of the prescribing physician. Appropriate dose ranges may bedetermined by methods known to those skilled in the art.

Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may be assayed invitro and in vivo for the desired therapeutic or prophylactic activityprior to use in humans. In vivo assays, for example using appropriateanimal models, may also be used to determine whether administration ofmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is therapeuticallyeffective.

In certain embodiments, a therapeutically effective dose of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may provide therapeuticbenefit without causing substantial toxicity including adverse sideeffects. Toxicity of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and/or metabolites thereof may be determined asdescribed herein and/or by using standard pharmaceutical procedures andmay be ascertained by those skilled in the art. The dose ratio betweentoxic and therapeutic effect is the therapeutic index. A dose of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may be within a rangecapable of establishing and maintaining a therapeutically effectivecirculating plasma and/or blood concentration of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate that exhibits little orno toxicity.

Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate administration maybe used to treat a disease chosen from adrenal leukodystrophy,AGE-induced genome damage, Alexander Disease, Alper's Disease,Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris,arthritis, asthma, balo concentric sclerosis, Canavan disease, cardiacinsufficiency including left ventricular insufficiency, central nervoussystem vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia withcentral nervous system hypomyelination, chronic idiopathic peripheralneuropathy, chronic obstructive pulmonary disease, Crohn's disease,diabetic retinopathy, graft versus host disease, hepatitis C viralinfection, herpes simplex viral infection, human immunodeficiency viralinfection, Huntington's disease, irritable bowel disorder, ischemia,Krabbe Disease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis and Zellweger's syndrome. The underlying etiology ofany of the foregoing diseases being treated may have a multiplicity oforigins. Further, in certain embodiments, a therapeutically effectiveamount of methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may beadministered to a patient, such as a human, as a preventative measureagainst the foregoing diseases and disorders. Thus, a therapeuticallyeffective amount of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be administered as a preventative measureto a patient having a predisposition for and/or history of adrenalleukodystrophy, AGE-induced genome damage, Alexander Disease, Alper'sDisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcott-Marie-Tooth Disease, childhoodataxia with central nervous system hypomyelination, chronic idiopathicperipheral neuropathy, chronic obstructive pulmonary disease, Crohn'sdisease, diabetic retinopathy, graft versus host disease, hepatitis Cviral infection, herpes simplex viral infection, human immunodeficiencyviral infection, Huntington's disease, irritable bowel disorder,ischemia, Krabbe Disease, lichen planus, macular degeneration,mitochondrial encephalomyopathy, monomelic amyotrophy, multiplesclerosis, myocardial infarction, neurodegeneration with brain ironaccumulation, neuromyelitis optica, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, paraneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilder's Disease, subacute necrotizing myelopathy, Susac'ssyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, and/or Zellweger's syndrome.

Administration

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate andpharmaceutical compositions thereof may be administered orally or by anyother appropriate route suitable for systemic or local administration.For example, systemic administration can be by infusion or bolusinjection, by absorption through epithelial or mucocutaneous linings(e.g., oral mucosa, rectal, and intestinal mucosa, etc.). Other suitableroutes of systemic administration include, but are not limited to,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual and inhalation. Localadministration can be topical (e.g., by applying a(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate-containingcream or lotion to an effected area of skin), or by localized injectioninto an effected organ (e.g., the eyeball).

The amount of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate that will be effective in the treatment of adisease in a patient will depend, in part, on the nature of thecondition and can be determined by standard clinical techniques known inthe art. In addition, in vitro or in vivo assays may be employed to helpidentify optimal dosage ranges. A therapeutically effective amount of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate to beadministered may also depend on, among other factors, the subject beingtreated, the weight of the subject, the severity of the disease, themanner of administration, and the judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose may beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information may be used to more accurately determineuseful doses in humans. One having ordinary skill in the art mayoptimize administration to humans based on animal data.

A dose may be administered in a single dosage form or in multiple dosageforms. When multiple dosage forms are used the amount of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate containedwithin each dosage form may be the same or different. The amount of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate containedin a dose may depend on the route of administration and whether thedisease in a patient is effectively treated by acute, chronic, or acombination of acute and chronic administration.

In certain embodiments an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) or the LD₁₀₀ (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may exhibit a high therapeutic index. The dataobtained from these cell culture assays and animal studies may be usedin formulating a dosage range that is not toxic for use in humans. Adose of (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateprovided by the present disclosure may be within a range of circulatingconcentrations in for example the blood, plasma, or central nervoussystem, that include the effective dose and that exhibits little or notoxicity. A dose may vary within this range depending upon the dosageform employed and the route of administration utilized. In certainembodiments, an escalating dose may be administered.

In some embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and pharmaceutical compositions thereof may beadministered orally or by any other appropriate route suitable forsystemic or local administration. For example, systemic administrationcan be by infusion or bolus injection, by absorption through epithelialor mucocutaneous linings (e.g., oral mucosa, rectal, and intestinalmucosa, etc.). Other suitable routes of systemic administration include,but are not limited to, intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual andinhalation. Local administration can be topical (e.g., by applying amethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate-containing creamor lotion to an effected area of skin), or by localized injection intoan effected organ (e.g., the eyeball).

The amount of methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate thatwill be effective in the treatment of a disease in a patient willdepend, in part, on the nature of the condition and can be determined bystandard clinical techniques known in the art. In addition, in vitro orin vivo assays may be employed to help identify optimal dosage ranges. Atherapeutically effective amount of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate to be administered may also depend on, amongother factors, the subject being treated, the weight of the subject, theseverity of the disease, the manner of administration, and the judgmentof the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose may beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information may be used to more accurately determineuseful doses in humans. One having ordinary skill in the art mayoptimize administration to humans based on animal data.

A dose may be administered in a single dosage form or in multiple dosageforms. When multiple dosage forms are used the amount of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate contained within eachdosage form may be the same or different. The amount of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate contained in a dose maydepend on the route of administration and whether the disease in apatient is effectively treated by acute, chronic, or a combination ofacute and chronic administration.

In certain embodiments an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) or the LD₁₀₀ (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may exhibit a high therapeutic index. The dataobtained from these cell culture assays and animal studies may be usedin formulating a dosage range that is not toxic for use in humans. Adose of methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate providedby the present disclosure may be within a range of circulatingconcentrations in for example the blood, plasma, or central nervoussystem, that include the effective dose and that exhibits little or notoxicity. A dose may vary within this range depending upon the dosageform employed and the route of administration utilized. In certainembodiments, an escalating dose may be administered.

Combination Therapy

Methods provided by the present disclosure further compriseadministering one or more pharmaceutically active compounds in additionto (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Suchcompounds may be provided to treat the same disease or a differentdisease than the disease being treated with the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In certain embodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be used in combination with DMF.

In certain embodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be used in combination with MMF.

In certain embodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be used in combination with methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In certain embodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be used in combination with at least oneother therapeutic agent. In certain embodiments,(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may beadministered to a patient together with another compound for treatingdiseases and conditions including: adrenal leukodystrophy, AlexanderDisease, Alper's Disease, balo concentric sclerosis, Canavan disease,central nervous system vasculitis, Charcott-Marie-Tooth Disease,childhood ataxia with central nervous system hypomyelination, diabeticretinopathy, graft versus host disease, hepatitis C viral infection,herpes simplex viral infection, human immunodeficiency viral infection,Krabbe Disease, lichen planus, macular degeneration, monomelicamyotrophy, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, optic neuritis, paraneoplasticsyndromes, Pelizaeus-Merzbacher disease, primary lateral sclerosis,progressive supranuclear palsy, Schilder's Disease, subacute necrotizingmyelopathy, Susac's syndrome, transverse myelitis, a tumor, andZellweger's syndrome.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and the atleast one other therapeutic agent may act additively or, and in certainembodiments, synergistically. The at least one additional therapeuticagent may be included in the same dosage form as(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate or may beprovided in a separate dosage form. Methods provided by the presentdisclosure can further include, in addition to administering(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate,administering one or more therapeutic agents effective for treating thesame or different disease than the disease being treated by(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. Methodsprovided by the present disclosure include administration of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and one ormore other therapeutic agents provided that the combined administrationdoes not inhibit the therapeutic efficacy of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and/or doesnot typically produce significant and/or substantial adverse combinationeffects.

In certain embodiments, dosage forms comprising(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same dosage form as, or in a differentdosage form than that comprising (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be administered prior or subsequent toadministration of another therapeutic agent. In certain embodiments, thecombination therapy may comprise alternating between administering(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and acomposition comprising another therapeutic agent, e.g., to minimizeadverse drug effects associated with a particular drug. When(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate isadministered concurrently with another therapeutic agent thatpotentially may produce an adverse drug effect including, but notlimited to, toxicity, the other therapeutic agent may advantageously beadministered at a dose that falls below the threshold at which theadverse drug reaction is elicited.

In certain embodiments, dosage forms comprising(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate may beadministered with one or more substances to enhance, modulate and/orcontrol release, bioavailability, therapeutic efficacy, therapeuticpotency, stability, and the like of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate. For example, to enhance the therapeuticefficacy of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate, the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be co-administered with or a dosage formcomprising (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioateand one or more active agents to increase the absorption or diffusion of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate from thegastrointestinal tract to the systemic circulation, or to inhibitdegradation of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in the blood of a patient. In certainembodiments, (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate may be co-administered with an active agenthaving pharmacological effects that enhance the therapeutic efficacy of(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In other embodiments, methods provided by the present disclosure furthercomprise administering one or more pharmaceutically active compounds inaddition to methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate. Suchcompounds may be provided to treat the same disease or a differentdisease than the disease being treated with the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be used in combination with DMF.

In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be used in combination with MMF.

In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be used in combination withN,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be used in combination with at least oneother therapeutic agent. In certain embodiments, methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may be administered to apatient together with another compound for treating diseases andconditions including: adrenal leukodystrophy, Alexander Disease, Alper'sDisease, balo concentric sclerosis, Canavan disease, central nervoussystem vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia withcentral nervous system hypomyelination, diabetic retinopathy, graftversus host disease, hepatitis C viral infection, herpes simplex viralinfection, human immunodeficiency viral infection, Krabbe Disease,lichen planus, macular degeneration, monomelic amyotrophy,neurodegeneration with brain iron accumulation, neuromyelitis optica,neurosarcoidosis, optic neuritis, paraneoplastic syndromes,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, Schilder's Disease, subacute necrotizing myelopathy,Susac's syndrome, transverse myelitis, a tumor, and Zellweger'ssyndrome.

Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate and the at leastone other therapeutic agent may act additively or, and in certainembodiments, synergistically. The at least one additional therapeuticagent may be included in the same dosage form as methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate or may be provided in aseparate dosage form. Methods provided by the present disclosure canfurther include, in addition to administering methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate, administering one ormore therapeutic agents effective for treating the same or differentdisease than the disease being treated by methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. Methods provided by the present disclosureinclude administration of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and one or more other therapeutic agentsprovided that the combined administration does not inhibit thetherapeutic efficacy of the methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and/or does not typically produce significantand/or substantial adverse combination effects.

In certain embodiments, dosage forms comprising methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may be administeredconcurrently with the administration of another therapeutic agent, whichmay be part of the same dosage form as, or in a different dosage formthan that comprising methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate. Methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be administered prior or subsequent toadministration of another therapeutic agent. In certain embodiments, thecombination therapy may comprise alternating between administeringmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate and a compositioncomprising another therapeutic agent, e.g., to minimize adverse drugeffects associated with a particular drug. When methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate is administeredconcurrently with another therapeutic agent that potentially may producean adverse drug effect including, but not limited to, toxicity, theother therapeutic agent may advantageously be administered at a dosethat falls below the threshold at which the adverse drug reaction iselicited.

In certain embodiments, dosage forms comprising methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may be administered withone or more substances to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, stability,and the like of methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.For example, to enhance the therapeutic efficacy of methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate, the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate may be co-administeredwith or a dosage form comprising methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate and one or more active agents to increase theabsorption or diffusion of methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate from the gastrointestinal tract to the systemiccirculation, or to inhibit degradation of the methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate in the blood of apatient. In certain embodiments, methyl 4-morpholin-4-ylbutyl(2E)but-2-ene-1,4-dioate may be co-administered with an active agenthaving pharmacological effects that enhance the therapeutic efficacy ofmethyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate.

EXAMPLES

The following examples illustrate various aspects of the disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the disclosure.

Example 1 Photodegradation of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate under cool white fluorescent Light

Approximately 50 mg (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate powder was spread into a thin layer (˜1 mm) inopen quartz containers. The sample was then placed in an ICH2Photoreactor (Luzchem Research Inc.) with 16 cool white fluorescentlamps (F8T5/CW—8 Watt) installed. The light power was 22.8×10³ lux withlow level of near UV light (320-400 nm) at 2.2 watt/m². The sample wastaken out after 53 hours to achieve a light exposure of 1.2 million luxhours. The sample solution was prepared at 0.2 mg/mL in diluent(water/acetonitrile/H₃PO₄ (80/20/0.05 by volume)).

To quantify the photodegratation of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate powder, the presence of(N,N-diethylcarbamoyl)methyl (1S, 3S, 2R,4R)-2-{[(N,N-diethylcarbamoyl)methyl]oxycarbonyl}-3,4-bis(methoxycarbonyl)cyclobutanecarboxylate(“compound (1)”) was quantified. The structure of compound (1) is shownbelow:

The amount (weight percent) of compound (1) in the sample was determinedby reverse phase HPLC using a C₁₈ column and a 30-minute gradient methodaccording to Table 1 where Mobile Phase A is water/0.05% H₃PO₄ andMobile Phase B is water/acetonitrile/H₃PO₄ (10/90/0.05 by volume) withUV detection at 210 nm. The amount of compound (1) found was 29.0 wt %.

TABLE 1 Gradient for HPLC Method Time (minutes) % Mobile Phase A %Mobile Phase B 0 98 2 6 65 35 15 55 45 25 10 90 25.1 98 2 30 98 2

Example 2 Photodegradation of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate under near-UV Light

Approximately 50 mg (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate powder was spread into a thin layer in openquartz containers. The sample was then placed in an ICH2 Photoreactor(Luzchem Research Inc.) with 16 near-UV fluorescent lamps (HitachiFL8BL-B) installed. The near-UV light (320-400 nm) power was 94.2watt/m². The sample was taken out after 2.1 hours to achieve a lightexposure of 200 watt hour/m². The sample was prepared and analyzed thesame way as described in Example 1. The amount of compound (1) found was10.3 wt %.

Example 3 Photodegradation of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in aqueous solution under cool whitefluorescent Light

A quartz flask containing approximately 20 mL of 0.1 mg/mL(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in 50 mM pH4.0 citrate buffer was placed in an ICH2 Photoreactor (Luzchem ResearchInc.) with 16 cool white fluorescent lamps (F8T5/CW—8 Watt) installed.The light power was 22.8×10³ lux with low level of near UV light(320-400 nm) at 2.2 watt/m². The sample was taken out after 53 hours toachieve a light exposure of 1.2 million lux hours.

To quantify the photodegratation of the (N,N-diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate powder, the presence of(N,N-diethylcarbamoyl)methyl methyl (2Z)but-2-ene-1,4-dioate (“compound(2)”) was quantified. The structure for compound (2) is shown below:

The sample was analyzed using the same HPLC method as described inExample 1. The amount of compound (2) found was 22.3 wt %.

Example 4 Photodegradation of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in aqueous solution under near-UV Light

A quartz flask containing approximately 20 mL of 0.1 mg/mL(NA-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in 50 mM pH4.0 citrate buffer was placed in an ICH2 Photoreactor (Luzchem ResearchInc.) with 16 near-UV fluorescent lamps (Hitachi FL8BL-B) installed. Thenear-UV light (320-400 nm) power was 94.2 watt/m². The sample was takenout after 2.1 hours to achieve a light exposure of 200 watt hour/m². Thesample was analyzed using the same HPLC method as described inExample 1. The amount of compound (2) found was 3.6 wt %.

Having described several embodiments, it will be recognized by thoseskilled in the art that various modifications, alternativeconstructions, and equivalents may be used without departing from thespirit of the disclosure. Additionally, a number of well-known processesand elements have not been described in order to avoid unnecessarilyobscuring the embodiments disclosed herein. Accordingly, the abovedescription should not be taken as limiting the scope of the document.

Those skilled in the art will appreciate that the presently disclosedembodiments teach by way of example and not by limitation. Therefore,the matter contained in the above description or shown in theaccompanying drawings should be interpreted as illustrative and not in alimiting sense. The following claims are intended to cover all genericand specific features described herein, as well as all statements of thescope of the present method and system, which, as a matter of language,might be said to fall there between.

We claim:
 1. A pharmaceutical dosage form comprising: (a) from about 1mg to about 600 mg (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate; and (b) one or more compounds of Formulae (I),(II), (III), (IV), (V), (VI), (XIII), (XV):

 and N,N-diethyl-2-hydroxyacetamide, wherein: each of R¹ through R⁴ isindependently chosen from hydrogen, methyl and (N,N-diethylcarbamoyl)methyl; each R⁵ and R⁷ is independently chosen from hydrogen,methyl, and (N,N-diethyl carbamoyl)methyl; Y is chosen from O, S, NH andNR⁸; R⁶ is chosen from hydrogen, lower alkyl, substituted lower alkyl,aryl, and substituted aryl; R⁸ is chosen from lower alkyl; each of R⁹and R¹⁰ is independently chosen from hydrogen, methyl, and(N,N-diethylcarbamoyl)methyl; each of R¹¹ and R¹² is independentlychosen from hydrogen, methyl, and (N,N-diethyl carbamoyl)methyl; each ofR¹³ and R¹⁴ is independently chosen from hydrogen, methyl, and(N,N-diethyl carbamoyl)methyl; Q is —O—, —S—, —NH—, N(R¹⁷)— or—C(R¹⁸)₂—; each of R¹⁵ and R¹⁶ is independently chosen from hydrogen,methyl, and (N,N-diethyl carbamoyl)methyl; R¹⁷ is(N,N-diethylcarbamoyl)methyl or alkyl; each R¹⁸ is independentlyhydrogen or alkyl; each of R³⁷ and R³⁸ is independently chosen fromhydrogen, methyl, and (N,N-diethylcarbamoyl)methyl; R⁴¹ is(N,N-diethylcarbamoyl)methyl; R⁴² is chosen from hydrogen, ethyl, and(N,N-diethylcarbamoyl)methyl; wherein the one or more compounds ofFormulae (I), (II), (III), (IV), (V), (VI), (XIII), (XV), andN,N-diethyl-2-hydroxyacetamide is present in a combined total amount of0.001% to 3% by weight based on total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, and theone or more compounds of Formula (I) is present in a combined amounttotal of less than 1.4% by weight based on the total weight of the(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; and andthe dosage form is a tablet.
 2. The dosage form of claim 1, wherein anyone of the one or more compounds of Formulae (I), (II), (III), (IV),(V), (VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide ispresent in a combined total amount of about 0.001% to about 2% by weightbased on total weight of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.
 3. The dosage form of claim 1, wherein any oneof the one or more compounds of Formulae (I), (II), (III), (IV), (V),(VI), (XIII), and (XV), and N,N-diethyl-2-hydroxyacetamide is present inan amount of about 0.001% to about 0.2% by weight based on total weightof the (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. 4.The dosage form of claim 1, including a pharmaceutically acceptablevehicle.
 5. The dosage form of claim 4, wherein the pharmaceuticallyacceptable vehicle is selected from a carrier, a diluent, an excipient,a wetting agent, an emulsifier, a buffer, a stabilizer, a thickener, alubricant, a coloring agent, and combinations thereof.
 6. The dosageform of claim 1 containing a compound of Formula (I), comprising anopaque layer that is free of the (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate.
 7. The dosage form of claim 1, wherein thetherapeutically effective amount of (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate is from about 100 mg to about 1 g per day.